U.S. patent number 7,402,577 [Application Number 10/491,403] was granted by the patent office on 2008-07-22 for androstane 17-beta-carboxamides as androgen receptor modulators.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Mark E. Duggan, Jiabing Wang, David B. Whitman.
United States Patent |
7,402,577 |
Wang , et al. |
July 22, 2008 |
Androstane 17-beta-carboxamides as androgen receptor modulators
Abstract
Compounds of structural formula as herein defined are disclosed
as useful in a method for modulating the androgen receptor in a
tissue selective manner in a patient in need of such modulation, as
well as in a method of activating the function of the androgen
receptor in a patient, and in particular the method wherein the
function of the androgen receptor is blocked in the prostate of a
male patient or in the uterus of a female patient and activated in
bone and/or muscle tissue. These compounds are useful in the
treatment of conditions caused by androgen deficiency or which can
be ameliorated by androgen administration, including osteoporosis,
periodontal disease, bone fracture, bone damage following bone
reconstructive surgery, sarcopenia, frailty, aging skin, male
hypogonadism, female sexual dysfunction, post-menopausal symptoms
in women, atherosclerosis, hypercholesterolemia, hyperlipidemia,
aplastic anemia and other hematopoietic disorders, pancreatic
cancer, renal cancer, prostate cancer, arthritis and joint repair,
alone or in combination with other active agents.
Inventors: |
Wang; Jiabing (Chalfont,
PA), Duggan; Mark E. (Schwenksville, PA), Whitman; David
B. (Phoenixville, PA) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
23274800 |
Appl.
No.: |
10/491,403 |
Filed: |
September 27, 2002 |
PCT
Filed: |
September 27, 2002 |
PCT No.: |
PCT/US02/30864 |
371(c)(1),(2),(4) Date: |
March 30, 2004 |
PCT
Pub. No.: |
WO03/029268 |
PCT
Pub. Date: |
April 10, 2003 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20040220159 A1 |
Nov 4, 2004 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60327024 |
Oct 3, 2001 |
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Current U.S.
Class: |
514/177; 552/611;
552/513 |
Current CPC
Class: |
A61P
9/10 (20180101); C07J 3/00 (20130101); A61P
31/18 (20180101); A61P 35/00 (20180101); A61P
37/06 (20180101); A61P 15/08 (20180101); A61K
31/568 (20130101); A61P 5/26 (20180101); A61P
21/00 (20180101); A61P 1/02 (20180101); A61K
31/663 (20130101); A61P 3/06 (20180101); A61P
3/00 (20180101); A61P 19/10 (20180101); A61K
31/56 (20130101); A61P 7/06 (20180101); A61K
31/663 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/56 (20060101); C07J 3/00 (20060101) |
Field of
Search: |
;514/177
;552/513,611 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 94/03474 |
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Feb 1994 |
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WO |
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WO 98/15568 |
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Apr 1998 |
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WO |
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WO 98/25623 |
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Jun 1998 |
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WO |
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Other References
Physicians' Desk Reference(PDR), Edition 61, 2007, p. 1973,
Montvale, NJ. cited by other .
Negro-Vilar, Andres, The Journal of Clinical Endocrinology &
Metabolism, "Selective Androgen Receptor Modulators (SARMs): A
Novel Approach to Androgen Therapy for the New Millenium," 1999,
pp. 3459-3462, vol. 84, No. 10, San Diego, CA. cited by other .
Chang, C., "Androgens and Androgen Receptor: Mechanisms, Functions,
and Clinical Applications," 2002, p. 279-288, Norwell, MA. cited by
other.
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Primary Examiner: Badio; Barbara P
Attorney, Agent or Firm: Panzer; Curtis C. Shatynski;
Patricia A. Camara; Valerie J.
Parent Case Text
This application is a U.S. national Phase application under 35.
U.S.C. .sctn. 371 of PCT Application No. PCT/US02/30864, filed Sep.
27, 2002, which claims priority under 35 U.S.C. 119 to U.S. Ser.
No. 60/327,024, filed Oct. 3, 2001.
Claims
What is claimed is:
1. A compound selected from the group consisting of:
(17.beta.)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide-
;
(17.beta.)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamid-
e;
(17.beta.)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxami-
de;
(17.beta.)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-ca-
rboxamide;
(17.beta.)-N-methyl-3-oxo-4-(2-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide;
(17.beta.)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-ca-
rboxamide;
(17.beta.)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide;
(17.beta.)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-
-carboxamide;
(17.beta.)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxam-
ide;
(17.beta.)-6.alpha.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide;
(17.beta.)-6.beta.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene--
17-carboxamide;
(17.beta.)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-1-
7-carboxamide;
(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-
cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide; and
(1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a, 10b,
10c-hexadecahydro-cyclopenta[a]cyclopropa[1]phenanthrene-8-carboxamide;
or a pharmaceutically acceptable salt thereof.
2. A composition comprising a compound according to claim 1 and a
pharmaceutically acceptable carrier.
Description
BACKGROUND OF THE INVENTION
The androgen receptor (AR) belongs to the superfamily of
steroid/thyroid hormone nuclear receptors, whose other members
include the estrogen receptor (ER), the progesterone receptor (PR),
the glucocorticoid receptor (GR), and the mineralocorticoid
receptor (MR). The AR is expressed in numerous tissues of the body
and is the receptor through which the physiological as well as the
pathophysiological effects of endogenous androgen ligands, such as
testosterone (T) and dihydrotestosterone (DHT), are expressed.
Structurally, the AR is composed of three main functional domains:
the ligand binding domain (LBD), the DNA-binding domain, and
amino-terminal domain. A compound that binds to the AR and mimics
the effects of an endogenous AR ligand is referred to as an AR
agonist, whereas a compound that inhibits the effects of an
endogenous AR ligand is termed an AR antagonist.
Androgen ligand binding to the AR affords a ligand/receptor
complex, which, subsequent to translocation inside the nucleus of
the cell, binds to specific regulatory DNA sequences (referred to
as androgen response elements or AREs) within the promoter or
enhancer regions of the target gene or genes present in the cell's
nucleus. Other proteins termed cofactors are next recruited which
bind to the amino-terminal domain or the LBD of the receptor
leading to gene transcription and subsequent translation to produce
the protein(s) encoded by that gene or genes.
Androgen therapy has been used in the clinic to treat a variety of
male disorders, such as reproductive disorders and primary or
secondary male hypogonadism. Moreover, a number of natural or
synthetic AR agonists have been clinically investigated for the
treatment of musculoskeletal disorders, such as bone disease,
hematopoietic disorders, neuromuscular disease, rheumatological
disease, wasting disease, and for hormone replacement therapy
(HRT), such as female androgen deficiency. In addition, AR
antagonists, such as flutamide and bicalutamide, have been used to
treat prostate cancer. It would therefore be useful to have
available compounds that can activate ("agonize") the function of
the AR in a tissue-selective manner which would afford the desired
beneficial osteoanabolic effects of androgens but without the
negative androgenic properties, such as virilization and induction
of an atherogenic lipid profile which can lead to cardiovascular
disease.
The role of androgens in bone formation has been documented. For
example, anabolic steroids, such as nandrolone decanoate or
stanozolol, have been shown to increase bone mass in postmenopausal
women. The beneficial effects of androgens on bone in
postmenopausal osteoporosis were documented in recent studies using
combined testosterone and estrogen administration [Hofbauer, et
al., "Androgen effects on bone metabolism: recent progress and
controversies," Eur. J. Endocrinol. 140: 271-286 (1999)]. Combined
treatment significantly increased the rate and extent of the rise
in bone mineral density (BMD) in the lumbar and hip regions,
relative to treatment with estrogen alone. Additionally,
estrogen-progestin combinations that incorporated an androgenic
progestin (such as norethindrone), rather than medroxyprogesterone
acetate, yielded greater improvements in hip BMD. These results
have recently been confirmed in a larger 2-year, double-blind
comparison study in which oral conjugated estrogen (CEE) and
methyltestosterone combinations were demonstrated to be effective
in promoting accrual of bone mass in the spine and hip, while
conjugated estrogen therapy alone prevented bone loss ["A two-year,
double-blind comparison of estrogen-androgen and conjugated
estrogens in surgically menopausal women: Effects on bone mineral
density, symptoms and lipid profiles," J. Reprod. Med., 44:
1012-1020 (1999)]. Despite the beneficial effects of androgens in
postmenopausal women, the use of androgens has been limited because
of the undesirable virilizing and metabolic action of androgens.
The data from Watts and colleagues demonstrate that hot flushes
decrease in women treated with CEE and methyltestosterone; however,
30% of these women suffered from significant increases in acne and
facial hair, a complication of all current androgen
pharmacotherapies [Watts, et al., "Comparison of oral estrogens and
estrogens plus androgen on bone mineral density, menopausal
symptoms, and lipid-lipoprotein profiles in surgical menopause,"
Obstet. Gynecol., 85: 529-537 (1995)]. Moreover, the addition of
methyltestosterone to CEE markedly decreased HDL levels, as seen in
other studies. Therefore, non-tissue selective AR agonists may
increase the risk of cardiovascular disease. Thus, the virilizing
potential and negative effects on lipid profile of current androgen
therapies provide a strong rationale for developing
tissue-selective androgen receptor agonists for bone. Reference is
made to J. A. Kanis, "Other agents for generalized osteoporosis,"
in Osteoporosis, Blackwell Science, Ch. 8, pp 196-227 (1994) for a
discussion of non-selective anabolic steroids in the treatment of
osteoporosis.
It is also well established that androgens play an important role
in bone metabolism in men, which parallels the role of estrogens in
women [Anderson, et al., "Androgen supplementation in eugonadal men
with osteoporosis--effects of six months of treatment on bone
mineral density and cardiovascular risk factors," Bone, 18: 171-177
(1996)]. Even in eugonadal men with established osteoporosis, the
therapeutic response to testosterone treatment provided additional
evidence that androgens exert important osteoanabolic effects. Mean
lumbar BMD increased from 0.799 gm/cm.sup.2 to 0.839 g/cm.sup.2, in
5 to 6 months in response to 250 mg of testosterone ester
administered intramuscularly every fortnight. A common scenario for
androgen deficiency occurs in men with stage D prostate cancer
(metastatic) who undergo androgen deprivation therapy (ADT).
Endocrine orchiectomy is achieved by long acting GnRH agonists,
while androgen receptor blockade is implemented with flutamide,
nilutamide, bicalutamide, or RU 58841 (AR antagonists). In response
to hormonal deprivation, these men suffered from hot flushes,
significant bone loss, weakness, and fatigue. In a recent pilot
study of men with stage D prostate cancer, osteopenia (50% vs. 38%)
and osteoporosis (38% vs. 25%) were more common in men who had
undergone ADT for greater than one year than the patients who did
not undergo ADT [Wei, et al., "Androgen deprivation therapy for
prostate cancer results in significant loss of bone density,"
Urology, 54: 607-611 (1999)]. Lumbar spine BMD was significantly
lower in men who had undergone ADT. Thus, in addition to the use of
tissue selective AR agonists for osteoporosis, tissue selective AR
antagonists in the prostate that lack antagonistic action in bone
and muscle may be useful agents for the treatment of prostate
cancer, either alone or as an adjunct to traditional ADT such as
with a GnRH agonist/antagonist [See also A. Stoch, et al., J. Clin.
Endocrin. Metab., 86: 2787-2791 (2001)].
There is a need for more effective agents to treat osteopenia and
osteoporosis in both men and women. Osteoporosis is characterized
by bone loss, resulting from an imbalance between bone resorption
(destruction) and bone formation, which starts in the fourth decade
and continues throughout life at the rate of about 1-4% per year
[Eastell, "Treatment of postmenopausal osteoporosis," New Engl. J.
Med., 338: 736 (1998)]. In the United States, there are currently
about 20 million people with detectable fractures of the vertebrae
due to osteoporosis. In addition, there are about 250,000 hip
fractures per year due to osteoporosis, associated with a 12%-20%
mortality rate within the first two years, while 30% of patients
require nursing home care after the fracture and many never become
fully ambulatory again. In postmenopausal women, estrogen
deficiency leads to increased bone resorption resulting in bone
loss in the vertebrae of around 5% per year, immediately following
menopause. Thus, first line treatment/prevention of this condition
is inhibition of bone resorption by bisphosphonates, estrogens,
selective estrogen receptor modulators (SERMs), and calcitonin.
However, inhibitors of bone resorption are not sufficient to
restore bone mass for patients who have already lost a significant
amount of bone. The increase in spinal BMD attained by
bisphosphonate treatment can reach 11% after 7 years of treatment
with alendronate. In addition, as the rate of bone turnover differs
from site to site, higher in the trabecular bone of the vertebrae
than in the cortex of the long bones, the bone resorption
inhibitors are less effectivein increasing hip BMD and preventing
hip fracture. Therefore, osteoanabolic agents, which increase
cortical bone formation and bone mass of long bones by stimulating
periosteal bone formation, would address an unmet need in the
treatment of osteoporosis especially for patients with high risk of
hip fractures. The osteoanabolic agents also complement the bone
resorption inhibitors that target the trabecular envelope, leading
to a biomechanically favorable bone structure (Schmidt, et al.,
"Anabolic steroid: Steroid effects on bone in women," In: J. P.
Bilezikian, et al., Ed., Principles of Bone Biology, San Diego:
Academic Press, 1996). Tissue-selective AR agonists with diminished
deleterious effects on the cardiovascular system and limited
virilizing potential may be useful as a monotherapy for the
prevention and/or treatment of female osteoporosis. In addition, a
compound with osteoanabolic properties in bone and muscle but with
reduced activity in the prostate and sex accessory tissues may be
useful for the prevention and/or treatment of male osteoporosis and
osteopenia in men, particularly elderly men.
Selective androgen receptor modulators may also be useful to treat
certain hematopoietic disorders. It is known that androgens
stimulate renal hypertrophy and erythropoietin (EPO) production.
Prior to the introduction of recombinant human EPO, androgens were
employed to treat anemia caused by chronic renal failure. In
addition, androgens at pharmacological doses were found to increase
serum EPO levels in anemic patients with non-severe aplastic anemia
and myelodysplastic syndromes but not in non-anemic patients.
Treatment modalities for anemia will require selective action such
as may be provided by selective androgen receptor modulators.
Non-steroidal compounds having androgen receptor modulating
properties were disclosed in U.S. Pat. Nos. 5,688,808; 5,696,130;
6,017,924; 6,093,821; WO 01/16139 (published 8 Mar. 2001); and WO
01/16108 (published 8 Mar. 2001), all assigned to Ligand
Pharmaceuticals, and in WO 01/27086, assigned to Kaken Pharm. Co.
Additional background for the rationale behind the development of
Selective Androgen Receptor Modulators is found in L. Zhi and E.
Martinborough in Ann. Rep. Med. Chem. 36: 169-180 (2001).
Non-steroidal SARMs were disclosed in J. P. Edwards, "New
Nonsteroidal Androgen Receptor Modulators Based on
4-(Trifluoromethyl)-2(1H)-Pyrrolidino[3,2-g]quinolinone," Bioorg.
Med. Chem. Lett., 8: 745-750 (1998) and in L. Zhi et al.,
"Switching Androgen Receptor Antagonists to Agonists by Modifying
C-ring Substituents on Piperidino[3,4-g]quinolinone," Bioorg. Med.
Chem. Lett., 9: 1009-1012 (1999).
There exists a need in the clinical art for more effective agents
that can elicit the positive responses of androgen replacement
therapy but without the undesired side effects of non-tissue
selective agonists of the AR. What is needed are compounds that can
produce the same positive responses as androgen replacement therapy
but without the undesired side effects. Also needed are androgenic
compounds that exert selective effects on different tissues of the
body. In this invention, we have identified compounds that function
as selective androgen receptor modulators (SARMs) using a series of
in vitro cell-assays that profile ligand mediated activation of AR,
such as (i) N-C interaction, (ii) transcriptional repression, and
(iii) transcriptional activation. SARM compounds in this invention,
identified with the methods listed above, exhibit tissue selective
AR agonism in vivo, i.e. agonism in bone (stimulation of bone
formation in a rodent model of osteoporosis) and antagonism in
prostate (minimal effects on prostate growth in castrated rodents
and antagonism of prostate growth induced by AR agonists).
The compounds of the present invention identified as SARMs are
useful to treat diseases or conditions caused by androgen
deficiency which can be ameliorated by androgen administration.
Such compounds are ideal for the treatment of osteoporosis in women
and men as a monotherapy or in combination with inhibitors of bone
resorption, such as bisphosphonates, estrogens, SERMs, cathepsin K
inhibitors, .alpha.v.beta.3 integrin receptor antagonists,
calcitonin, and proton pump inhibitors. They can also be used with
agents that stimulate bone formation, such as parathyroid hormone
or analogs thereof. The SARM compounds of the present invention may
also be employed for treatment of prostate disease, such as
prostate cancer and benign prostatic hyperplasia (BPH). Moreover,
compounds of this invention exhibit minimal effects on skin (acne
and facial hair growth) and may be useful for treatment of
hirsutism. Additionally, compounds of this invention can stimulate
muscle growth and may be useful for treatment of sarcopenia and
frailty. Moreover, compounds of this invention can exhibit androgen
agonism in the central nervous system and may be useful to treat
vasomotor symptoms (hot flush) and to increase energy and libido,
particularly in postmenopausal women. The compounds of the present
invention may be used in the treatment of prostate cancer, either
alone or as an adjunct to traditional GnRH agonist/antagonist
therapy, for their ability to restore bone, or as a replacement for
antiandrogen therapy because of their ability to antagonize
androgen in the prostate, and minimize bone depletion in the
skeletal system. Further, the compounds of the present invention
may be used for their ability to restore bone in the treatment of
pancreatic cancer as an adjunct to treatment with antiandrogen, or
as monotherapy for their antiandrogenic properties, offering the
advantage over traditional antiandrogens of being bone-sparing.
Additionally, compounds of this invention can increase the number
of blood cells, such as red blood cells and platelets, and may be
useful for the treatment of hematopoietic disorders, such as
aplastic anemia. Finally, compounds of this invention have minimal
effects on lipid metabolism. Thus, considering their tissue
selective androgen receptor agonism listed above, the compounds of
this invention are ideal for hormone replacement therapy in
hypogonadic (androgen deficient) men.
It is therefore an object of the present invention to provide
androstane 17.beta.-carboxamide derivatives which are useful as
selective androgen receptor modulators.
It is another object of the present invention to provide
pharmaceutical compositions comprising the compounds of the present
invention in association with a pharmaceutically acceptable
carrier.
It is another object of the present invention to provide
pharmaceutical compositions comprising the steroid derivatives for
use as selective androgen receptor modulators.
It is another object of the present invention to provide methods
for the treatment of diseases or conditions caused by androgen
deficiency which can be ameliorated by androgen administration.
It is another object of the present invention to provide methods
for the treatment of diseases or conditions caused by androgen
deficiency which can be ameliorated by androgen administration in
combination with other agents.
It is another object of the present invention to provide androstane
17.beta.-carboxamide derivatives of the present invention and their
pharmaceutical compositions for use as a medicament for the
treatment of diseases or conditions caused by androgen deficiency
which can be ameliorated by androgen administration.
It is another object of the present invention to provide androstane
17.beta.-carboxamide derivatives of the present invention and their
pharmaceutical compositions for the manufacture of a medicament for
the treatment of diseases or conditions caused by androgen
deficiency which can be ameliorated by androgen administration.
These and other objects will become readily apparent from the
detailed description which follows.
SUMMARY OF THE INVENTION
The present invention provides a method for modulating a function
mediated by the androgen receptor in a tissue selective manner in a
patient in need of such modulation, comprising administering to the
patient a therapeutically effective amount of a compound of
structural formula I:
##STR00001## or a pharmaceutically acceptable salt thereof; wherein
"a" represents a single bond or a double bond; R.sup.1 is selected
from the group consisting of hydrogen, C.sub.1-3 alkyl, C.sub.3-6
cycloalkyl, phenyl, and phenyl C.sub.1-3 alkyl; in which alkyl,
cycloalkyl, and phenyl are unsubstituted or substituted with one to
three groups independently selected from halogen, hydroxy, amino,
carboxy, and C.sub.1-4 alkoxy; R.sup.2 and R.sup.3 are each
independently selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, hydroxy, C.sub.1-4 alkoxy, halogen, halogen C.sub.1-4
alkyl, carboxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkyloxycarbonyl, C.sub.1-6 alkylcarbonyloxy,
(C.sub.1-6).sub.0-2aminocarbonyloxy, in which alkyl, alkenyl,
alkynyl, and cycloalkyl are unsubstituted or substituted with one
to three substituents independently selected from halogen, hydroxy,
carboxy, and C.sub.1-4 alkoxy; or R.sup.2 and R.sup.3 are taken
together with the carbon atom to which they are attached to form a
carbonyl group, a C.sub.1-6 alkylidene group, or a spiro-C.sub.3-6
cycloalkyl group, unsubstituted or substituted with C.sub.1-4
alkyl; or R.sup.2 and R7 are taken together with the carbon atoms
to which they are attached to form a cyclopropyl group; R.sup.4 is
hydrogen or C.sub.1-4 alkyl; R.sup.5 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, and
phenyl C.sub.1-3 alkyl; R.sup.6 is aryl wherein the aryl group is
selected from the group consisting of (1) phenyl, (2) naphthyl, (3)
benzimidazolyl, (4) benzofuranyl, (5) benzothiophenyl, (6)
benzoxazolyl, (7) benzothiazolyl, (8) benzodihydrofuranyl, (9)
indolyl, (10) quinolyl, (11) isoquinolyl, (12) furanyl, (13)
thienyl, (14) imidazolyl, (15) oxazolyl, (16) thiazolyl, (17)
isoxazolyl, (18) isothiazolyl, (19) pyrazolyl, (20) pyrrolyl, (21)
pyridyl, (22) pyrimidyl, (23) pyrazinyl, (24) thiadiazolyl, (25)
oxadiazolyl, (26) triazolyl, and (27) tetrazolyl; wherein the aryl
group as defined above items (1) to (27) is unsubstituted or
substituted with one to three substituents independently selected
from halogen, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8
cycloheteroalkyl, phenyl, phenyl C.sub.1-3 alkyl, amino, amino
C.sub.1-6 alkyl, C.sub.1-3 acylamino, C.sub.1-3 acylamino C.sub.1-6
alkyl, C.sub.1-6 alkylamino, di-(C.sub.1-6 alkyl)amino,
di-(C.sub.1-6 alkyl)amino C.sub.1-6 alkyl, C.sub.1-6 alkylamino
C.sub.1-6 alkyl, aminocarbonylamino, C.sub.1-4 alkoxy, C.sub.1-4
alkoxy C.sub.1-6 alkyl, C.sub.1-4 alkylthio, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylsulfonylamino, carboxy, carboxy C.sub.1-6 alkyl, C.sub.1-5
alkoxycarbonyl, C.sub.1-3 alkoxycarbonyl C.sub.1-6 alkyl, C.sub.1-5
alkylcarbonyloxy, hydroxy, hydroxy C.sub.1-6 alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, and trifluoroethoxy; and R.sup.7
is hydrogen or C.sub.1-4 alkyl.
The present invention is also concerned with a method of activating
the function of the androgen receptor in a patient, and, in
particular, a method wherein the function of the androgen receptor
is activated (agonized) in bone and/or muscle tissue and blocked in
the prostate of a male patient or in the uterus of a female patient
with a compound of structural formula I. The compounds of formula I
are useful in the prevention and/or treatment of diseases or
conditions caused by androgen deficiency or which can be
ameliorated by androgen replacement. These diseases or conditions
include osteoporosis, periodontal disease, bone fracture, bone
damage following bone reconstructive surgery, sarcopenia, frailty,
aging skin, male hypogonadism, post-menopausal symptoms in women,
atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic
anemia and other hematopoietic disorders, pancreatic cancer,
inflammatory arthritis and joint repair. The compounds of the
present invention may be used alone or in combination with other
active agents. In particular, the compounds of the present
invention are useful for the prevention and/or treatment of male
and female osteoporosis.
The present invention is also concerned with novel compounds which
are selective androgen receptor modulators, pharmaceutical
compositions containing these novel compounds in association with a
pharmaceutically acceptable carrier, and methods to treat diseases
or conditions caused by androgen deficiency or which can be
ameliorated by androgen replacement with the novel compounds of the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for modulating a function
mediated by the androgen receptor in a tissue selective manner in a
patient in need of such modulation, comprising administering to the
patient a therapeutically effective amount of a compound of
structural formula I:
##STR00002## or a pharmaceutically acceptable salt thereof; wherein
"a" represents a single bond or a double bond; R.sup.1 is selected
from the group consisting of hydrogen, C.sub.1-3 alkyl, C.sub.3-6
cycloalkyl, phenyl, and phenyl C.sub.1-3 alkyl; in which alkyl,
cycloalkyl, and phenyl are unsubstituted or substituted with one to
three groups independently selected from halogen, hydroxy, amino,
carboxy, and C.sub.1-4 alkoxy; R.sup.2 and R.sup.3 are each
independently selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6
cycloalkyl, hydroxy, C.sub.1-14 alkoxy, halogen, halogen C.sub.1-4
alkyl, carboxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkyloxycarbonyl, C.sub.1-6 alkylcarbonyloxy,
(C.sub.1-6).sub.0-2aminocarbonyloxy, in which alkyl, alkenyl,
alkynyl, and cycloalkyl are unsubstituted or substituted with one
to three substituents independently selected from halogen, hydroxy,
carboxy, and C.sub.1-4 alkoxy; or R.sup.2 and R.sup.3 are taken
together with the carbon atom to which they are attached to form a
carbonyl group, a C.sub.1-6 alkylidene group, or a spiro-C.sub.3-6
cycloalkyl group, unsubstituted or substituted with C.sub.1-4
alkyl; or R.sup.2 and R.sup.7 are taken together with the carbon
atoms to which they are attached to form a cyclopropyl group;
R.sup.4 is hydrogen or C.sub.1-4 alkyl; R.sup.5 is selected from
the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, and phenyl C.sub.1-3 alkyl; R.sup.6 is aryl wherein the
aryl group is selected from the group consisting of (1) phenyl, (2)
naphthyl, (3) benzimidazolyl, (4) benzofuranyl, (5)
benzothiophenyl, (6) benzoxazolyl, (7) benzothiazolyl, (8)
benzodihydrofuranyl, (9) indolyl, (10) quinolyl, (11) isoquinolyl,
(12) furanyl, (13) thienyl, (14) imidazolyl, (15) oxazolyl, (16)
thiazolyl, (17) isoxazolyl, (18) isothiazolyl, (19) pyrazolyl, (20)
pyrrolyl, (21) pyridyl, (22) pyriridyl, (23) pyrazinyl, (24)
thiadiazolyl, (25) oxadiazolyl, (26) triazolyl, and (27)
tetrazolyl; wherein the aryl group as defined above items (1) to
(27) is unsubstituted or substituted with one to three substituents
independently selected from halogen, C.sub.1-8 alkyl, C.sub.3-8
cycloalkyl, C.sub.3-8 cycloheteroalkyl, phenyl, phenyl C.sub.1-3
alkyl, amino, amino C.sub.1-6 alkyl, C.sub.1-3 acylamino, C.sub.1-3
acylamino C.sub.1-6 alkyl, C.sub.1-6 alkylamino, di-(C.sub.1-6
alkyl)amino, di-(C.sub.1-6 alkyl)amino C.sub.1-6 alkyl, C.sub.1-6
alkylamino C.sub.1-6 alkyl, aminocarbonylamino, C.sub.1-4 alkoxy,
C.sub.1-4 alkoxy C.sub.1-6 alkyl, C.sub.1-4 alkylthio, C.sub.1-4
alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4
alkylsulfonylamino, carboxy, carboxy C.sub.1-6 alkyl, C.sub.1-5
alkoxycarbonyl, C.sub.1-3 alkoxycarbonyl C.sub.1-6 alkyl, C.sub.1-5
alkylcarbonyloxy, hydroxy, hydroxy C.sub.1-6 alkyl, cyano, nitro,
trifluoromethyl, trifluoromethoxy, and trifluoroethoxy; and R.sup.7
is hydrogen or C.sub.1-4 alkyl.
In one embodiment of the compounds useful in the methods of the
present invention, "a" represents a double bond and R.sup.7 is
hydrogen or methyl. In a class of this embodiment, R.sup.1 is
hydrogen or C.sub.1-3 alkyl.
In a second embodiment of the compounds useful in the methods of
the present invention, R.sup.4 is hydrogen.
In a third embodiment of the compounds useful in the methods of the
present invention, R.sup.5 is hydrogen or methyl and R.sup.6 is
selected from the group consisting of phenyl, naphthyl, and
pyridyl, unsubstituted or substituted with one to three groups
independently selected from halogen, nitro, trifluoromethyl,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, and cyano. In a class of this
embodiment, R.sup.6 is phenyl, unsubstituted or substituted with
one to three groups independently selected from halogen, nitro,
trifluoromethyl, methyl, methoxy, and cyano.
In a fourth embodiment of the compounds useful in the methods of
the present invention, R.sup.2 and R.sup.3 are each hydrogen or are
taken together with the carbon to which they are attached to form a
spirocyclopropyl or a methylene group.
In a fifth embodiment of the compounds useful in the methods of the
present invention, R.sup.2 and R.sup.7 are taken together with the
carbon atoms to which they are attached to form a fused cyclopropyl
ring.
In yet a further embodiment of the compounds useful in the methods
of the present invention are those represented by structural
formula II:
##STR00003## or a pharmaceutically acceptable salt thereof; wherein
R.sup.2 and R.sup.3 are hydrogen or R.sup.2 and R.sup.3 are taken
together with the carbon atom to which they are attached to form a
methylene or a spirocyclopropyl group; R.sup.5 is hydrogen or
methyl; R.sup.6 is phenyl, naphthyl, or pyridyl, unsubstituted or
substituted with one to three groups independently selected from
halogen, C.sub.1-4 alkyl, amino, C.sub.1-3 acylamino, C.sub.1-4
alkylamino, di-(C.sub.1-4 alkyl)amino, C.sub.1-4 alkoxy, C.sub.1-4
alkylthio, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfonylamino,
carboxy, C.sub.1-5 alkoxycarbonyl, C.sub.1-5 alkylcarbonyloxy,
hydroxy, cyano, nitro, and trifluoromethyl; and R.sup.7 is hydrogen
or methyl.
Illustrative but non-limiting examples of compounds useful in the
methods of the present invention are the following:
(17.beta.)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide-
;
(17.beta.)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamid-
e;
(17.beta.)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxami-
de;
(17.beta.)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-3-oxo-N-phenylandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-ca-
rboxamide;
(17.beta.)-N-methyl-3-oxo-4-(2-trifluorometylphenyl)-androst-4--
ene-17-carboxamide;
(17.beta.)-N-ethyl-3-oxo-4-(2-trifluorophenylphenyl)-androst-4-ene-17-car-
boxamide;
(17.beta.)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4--
ene-17-carboxamide;
(17.beta.)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-ca-
rboxamide;
(17.beta.)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-andros-
t-4-ene-17-carboxamide;
(17.beta.)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxam-
ide;
(17.beta.)-6.alpha.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide;
(17.beta.)-6.beta.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene--
17-carboxamide; and
(17.beta.)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-1-
7-carboxamide; or a pharmaceutically acceptable salt thereof.
Further illustrative but non-limiting examples of compounds useful
in the methods of the present invention are the following:
##STR00004##
(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide
##STR00005## and
(1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide.
The present invention also provides the following novel compounds
which are useful as selective androgen receptor modulators:
(17.beta.)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide-
;
(17.beta.)-3-oxo-N-(3-trifluoromethylphenyl)-androst-4-ene-17-carboxamid-
e;
(17.beta.)-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17-carboxami-
de;
(17.beta.)-N-(2-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-methoxyphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-chlorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-methylphenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(4-fluorophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-bromophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(2-iodophenyl)-3-oxoandrost-4-ene-17-carboxamide;
(17.beta.)-N-(3-methoxy-5-trifluoromethylphenyl)-3-oxoandrost-4-ene-17-ca-
rboxamide;
(17.beta.)-N-methyl-3-oxo-4-(2-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide;
(17.beta.)-N-ethyl-3-oxo-4-(2-trifluoromethylphenyl)-androst-4-ene-17-car-
boxamide;
(17.beta.)-4-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4--
ene-17-carboxamide;
(17.beta.)-7-methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-ca-
rboxamide;
(17.beta.)-6-methylene-3-oxo-N-(4-trifluoromethylphenyl)-andros-
t-4-ene-17-carboxamide;
(17.beta.)-N-(4-fluorophenyl)-6-methylene-3-oxo-androst-4-ene-17-carboxam-
ide;
(17.beta.)-6.alpha.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide;
(17.beta.)-6.beta.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene--
17-carboxamide;
(17.beta.)-6,6-ethyleno-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-1-
7-carboxamide;
(1aR,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide; and
(1aS,5aR,7aS,8S,10cR)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide; or a pharmaceutically acceptable
salt thereof.
The term "alkyl" shall mean straight or branched chain alkanes of
one to ten total carbon atoms, or any number within this range
(i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl,
t-butyl, etc.). The term "C.sub.0 alkyl" (as in "C.sub.0-8
alkylaryl") shall refer to the absence of an alkyl group.
The term "alkenyl" shall mean straight or branched chain alkenes of
two to ten total carbon atoms, or any number within this range.
The term "alkynyl" shall mean straight or branched chain alkynes of
two to ten total carbon atoms, or any number within this range.
The term "alkylidene" shall mean a straight or branched chain
alkylidene group of one to ten total carbon atoms, or any number
within this range.
The term "cycloalkyl" shall mean cyclic rings of alkanes of three
to eight total carbon atoms, or any number within this range (i.e.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl).
The term "cycloheteroalkyl," as used herein, shall mean a 3- to
8-membered fully saturated heterocyclic ring containing one or two
heteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl
groups include, but are not limited to, piperidinyl, pyrrolidinyl,
azetidinyl, morpholinyl, and piperazinyl. In one embodiment of the
present invention, cycloheteroalkyl is selected from piperidinyl,
pyrrolidinyl, and morpholinyl.
The term "alkoxy," as used herein, refers to straight or branched
chain alkoxides of the number of carbon atoms specified (e.g.,
C.sub.1-5 alkoxy), or any number within this range (i.e., methoxy,
ethoxy, etc.).
The term "aryl," as used herein, refers to a monocyclic or bicyclic
system comprising at least one aromatic ring, wherein the monocylic
or bicyclic system contains 0, 1, 2, 3, or 4 heteroatoms chosen
from N, O, or S, and wherein the monocylic or bicylic system is
either unsubstituted or substituted with one or more groups
independently selected from halogen, aryl, C.sub.1-8 alkyl,
C.sub.3-8 cycloalkyl, C.sub.3-8 cycloheteroalkyl, aryl
C.sub.1-6alkyl, amino C.sub.0-6alkyl, C.sub.1-6 alkylamino
C.sub.0-6alkyl, (C.sub.1-6 alkyl).sub.2amino C.sub.0-6alkyl, aryl
C.sub.0-6 alkylamino C.sub.0-6alkyl, (aryl C.sub.0-6
alkyl).sub.2amino C.sub.0-6alkyl, C.sub.1-6 alkylthio, aryl
C.sub.0-6alkylthio, C.sub.1-6 alkylsulfinyl, aryl
C.sub.0-6alkylsulfinyl, C.sub.1-6 alkylsulfonyl, aryl
C.sub.0-6alkylsulfonyl, C.sub.1-6 alkoxy C.sub.0-6alkyl, aryl
C.sub.0-6 alkoxy C.sub.0-6alkyl, hydroxycarbonyl C.sub.0-6alkyl,
C.sub.1-6 alkoxycarbonyl C.sub.0-6alkyl, aryl C.sub.0-6
alkoxycarbonyl C.sub.0-6alkyl, hydroxycarbonyl C.sub.1-6 alkyloxy,
hydroxy C.sub.0-6alkyl, cyano, nitro, perfluoroC.sub.1-4alkyl,
perfluoroC.sub.1-4alkoxy, oxo, C.sub.1-6 alkylcarbonyloxy, aryl
C.sub.0-6alkylcarbonyloxy, C.sub.1-6 alkylcarbonylamino, aryl
C.sub.0-6 alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aryl
C.sub.0-6alkylsulfonylamino, C.sub.1-6 alkoxycarbonylamino, aryl
C.sub.0-6 alkoxycarbonylamino, C.sub.1-6alkylaminocarbonylamino,
aryl C.sub.0-6alkylaminocarbonylamino, (C.sub.1-6alkyl).sub.2
aminocarbonylamino, (aryl C.sub.0-6alkyl).sub.2 aminocarbonylamino,
(C.sub.1-6alkyl).sub.2 aminocarbonyloxy, and (aryl
C.sub.0-6alkyl).sub.2 aminocarbonyloxy. Examples of aryl include,
but are not limited to, phenyl, naphthyl, pyridyl, pyrrolyl,
pyrazolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl,
benzthiazolyl, benzoxazolyl, indolyl, thienyl, furyl,
dihydrobenzofuryl, benzo(1,3)dioxolanyl, benzo(1,4)dioxanyl,
oxazolyl, isoxazolyl, thiazolyl, quinolinyl, and isothiazolyl,
which are either unsubstituted or substituted with one or more
groups independently selected from halogen, aryl, C.sub.1-8 alkyl,
C.sub.3-8 cycloalkyl, C.sub.3-8 cycloheteroalkyl, aryl
C.sub.1-6alkyl, amino C.sub.0-6alkyl, C.sub.1-6 alkylamino
C.sub.0-6alkyl, (C.sub.1-6 alkyl).sub.2amino C.sub.0-6alkyl, aryl
C.sub.0-6 alkylamino C.sub.0-6alkyl, (aryl C.sub.0-6
alkyl).sub.2amino C.sub.0-6alkyl, C.sub.1-6 alkylthio, aryl
C.sub.0-6alkylthio, C.sub.1-6 alkylsulfinyl, aryl
C.sub.0-6alkylsulfinyl, C.sub.1-6 alkylsulfonyl, aryl
C.sub.0-6alkylsulfonyl, C.sub.1-6 alkoxy C.sub.0-6alkyl, aryl
C.sub.0-6 alkoxy C.sub.0-6alkyl, hydroxycarbonyl C.sub.0-6alkyl,
C.sub.1-6 alkoxycarbonyl C.sub.0-6alkyl, aryl C.sub.0-6
alkoxycarbonyl C.sub.0-6alkyl, hydroxycarbonyl C.sub.1-6 alkyloxy,
hydroxy C.sub.0-6alkyl, cyano, nitro, perfluoroC.sub.1-4alkyl,
perfluoroC.sub.1-4alkoxy, oxo, C.sub.1-6 alkylcarbonyloxy, aryl
C.sub.0-6alkylcarbonyloxy, C.sub.1-6 alkylcarbonylamnino, aryl
C.sub.0-6 alkylcarbonylamino, C.sub.1-6 alkylsulfonylamino, aryl
C.sub.0-6alkylsulfonylamino, C.sub.1-6 alkoxycarbonylamino, aryl
C.sub.0-6 alkoxycarbonylamino, C.sub.1-6alkylaaminocarbonylamino,
aryl C.sub.0-6alkylaminocarbonylamino, (C.sub.1-6alkyl).sub.2
aminocarbonylamino, (aryl C.sub.0-6alkyl).sub.2 aminocarbonylamino,
(C.sub.1-6alkyl).sub.2 aminocarbonyloxy, and (aryl
C.sub.0-6alkyl).sub.2 aminocarbonyloxy. In one embodiment of the
present invention, aryl is selected from phenyl, pyridyl,
pyrazolyl, benzamidazolyl, imidazolyl, furyl, napthyl, indolyl, and
quinolinyl. Preferably, the aryl group is unsubstituted, mono-,
di-, or tri-substituted with one to three of the above-named
substituents; more preferably, the aryl group is unsubstituted,
mono- or di-substituted with one to two of the above-named
substituents.
Whenever the term "alkyl" or "aryl" or either of their prefix roots
appears in a name of a substituent (e.g., aryl C.sub.0-8 alkyl), it
shall be interpreted as including those limitations given above for
"alkyl" and "aryl." Designated numbers of carbon atoms (e.g.,
C.sub.0-8) shall refer independently to the number of carbon atoms
in an alkyl or cyclic alkyl moiety or to the alkyl portion of a
larger substituent in which alkyl appears as its prefix root.
The terms "arylalkyl" and "alkylaryl" include an alkyl portion
where alkyl is as defined above and include an aryl portion where
aryl is as defined above. Examples of arylalkyl include, but are
not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl,
phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl,
thienylethyl, and thienylpropyl. Examples of alkylaryl include, but
are not limited to, toluene, ethylbenzene, propylbenzene,
methylpyridine, ethylpyridine, propylpyridine and
butylpyridine.
The term "halogen" shall include iodine, bromine, chlorine, and
fluorine.
The term "oxy" means an oxygen (O) atom. The term "thio" means a
sulfur (S) atom. The term "oxo" means ".dbd.O". The term "carbonyl"
means "C.dbd.O."
The term "substituted" shall be deemed to include multiple degrees
of substitution by a named substitutent. Where multiple substituent
moieties are disclosed or claimed, the substituted compound can be
independently substituted by one or more of the disclosed or
claimed substituent moieties, singly or plurally. By independently
substituted, it is meant that the (two or more) substituents can be
the same or different.
When any variable (e.g., R.sup.3, R.sup.4, etc.) occurs more than
one time in any substituent or in formula I, its definition in each
occurrence is independent of its definition at every other
occurrence. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
Under standard nonmenclature used throughout this disclosure, the
terminal portion of the designated side chain is described first,
followed by the adjacent functionality toward the point of
attachment. For example, a C.sub.1-5 alkylcarbonylamino C.sub.1-6
alkyl substituent is equivalent to
##STR00006##
In choosing compounds of the present invention, one of ordinary
skill in the art will recognize that the various substituents, i.e.
R.sup.1, R.sup.2, R.sup.3, etc., are to be chosen in conformity
with well-known principles of chemical structure connectivity.
Compounds of the present invention have been found to be
tissue-selective modulators of the androgen receptor (SARMs). In
one aspect, compounds of the present invention may be useful to
activate the function of the androgen receptor in a patient, and in
particular to activate the function of the androgen receptor in
bone and/or muscle tissue and block or inhibit ("antagonize") the
function of the androgen receptor in the prostate of a male patient
or in the uterus of a female patient. The activation of the AR in
bone can be assayed through stimulation of bone formation in a
rodent model of osteoporosis, and the antagonism of the AR in the
prostate can be assayed through observation of minimal effects on
prostate growth in castrated rodents and antagonism of prostate
growth induced by AR agonists, as detailed in the Examples. A
further aspect of the present invention is concerned with compounds
of structural formula I that block the function of the androgen
receptor in the prostate of a male patient or in the uterus of a
female patient induced by AR agonists, but not in hair-growing skin
or vocal cords, and activate the function of the androgen receptor
in bone and/or muscle tissue, but not in organs which control blood
lipid levels (e.g. liver).
The compounds of the present invention may be used to treat and/or
prevent conditions in a male subject which are caused by androgen
deficiency or which can be ameliorated by androgen replacement,
including, but not limited to osteoporosis, osteopenia,
glucocorticoid-induced osteoporosis, periodontal disease, bone
fracture, bone damage following bone reconstructive surgery,
sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal
symptoms in women, atherosclerosis, hypercholesterolemia,
hyperlipidemia, aplastic anemia and other hematopoietic disorders,
inflammatory arthritis and joint repair, HIV-wasting, cancer
cachexia, muscular dystrophies, premature ovarian failure, and
autoimmune disaease, alone or in combination with other active
agents. Treatment is effected by administration of a
therapeutically effective amount of the compound of structural
formula I to a patient in need of such treatment.
In one embodiment, the compounds of the present invention may be
used to treat and/or prevent conditions in a male subject which are
caused by androgen deficiency or which can be ameliorated by
androgen replacement, including, but not limited to, osteoporosis,
osteopenia, glucocorticoid-induced osteoporosis, periodontal
disease, HIV-wasting, cancer cachexia, aplastic and other anemias,
and muscular dystrophies, alone or in combination with other active
agents. Treatment is effected by administration of a
therapeutically effective amount of the compound of structural
formula I to a male patient in need of such treatment.
In another embodiment, the compounds of the present invention may
be used to treat and/or prevent conditions in a female subject
which are caused by androgen deficiency or which can be ameliorated
by androgen replacement, including, but not limited to,
osteoporosis, osteopenia, glucocorticoid-induced osteoporosis,
periodontal disease, HIV-wasting, cancer cachexia, aplastic and
other anemias, muscular dystrophies, premature ovarian failure, and
autoimmune disease, alone or in combination with other active
agents. Treatment is effected by administration of a
therapeutically effective amount of the compound of structural
formula I to a female patient in need of such treatment.
The compounds of structural formula I may also be employed as
adjuncts to traditional androgen depletion therapy in the treatment
of prostate cancer to restore bone, minimize bone loss, and
maintain bone mineral density. In this manner, they may be employed
together with traditional androgen deprivation therapy, including
GnRH agonists/antagonists, such as those disclosed in P. Limonta,
et al., "LHRH analogues as anticancer agents: pituitary and
extrapituitary sites of action," Exp. Opin. Invest. Drugs, 10:
709-720 (2001); H. J. Stricker, "Luteinizing hormone-releasing
hormone antagonists," Urology, 58 (Suppl. 2A): 24-27 (2001); R. P.
Millar, et al., "Progress towards the development of non-peptide
orally-active GnRH antagonists," British Medical Bulletin, 56:
761-772 (2000); and A. V. Schally et al., "Rational use of agonists
and antagonists of LH-RH in the treatment of hormone-sensitive
neoplasms and gynecologic conditions," Advanced Drug Delivery
Reviews, 28: 157-169 (1997). It is also possible that the compounds
of structural formula I may be used in combination with
antiandrogens, such as flutamide, 2-hydroxyflutamide (the active
metabolite of flutamide), nilutamide, and bicalutamide
(Casodex.TM.) in the treatment of prostate cancer.
Further, the compounds of the present invention may also be
employed in the treatment of pancreatic cancer, either for their
androgen antagonist properties or as an adjunct to an antiandrogen,
such as flutamide, 2-hydroxyflutamide (the active metabolite of
flutamide), nilutamide, and bicalutamide (Casodex.TM.).
Compounds of structural formula I have minimal negative effects on
lipid metabolism. Therefore, considering their tissue selective
androgen agonistic properties, the compounds of this invention have
advantages over existing approaches for hormone replacement therapy
in hypogonadic (androgen deficient) men.
Additionally, compounds of the present invention can increase the
number of blood cells, such as red blood cells and platelets, and
can be used for treatment of hematopoietic disorders, such as
aplastic anemia.
Representative compounds of the present invention typically display
submicromolar binding affinity for the androgen receptor. Compounds
of this invention are therefore useful in treating mammals
suffering from disorders related to androgen receptor function.
Pharmacologically effective amounts of the compound, including the
pharmaceutically effective salts thereof, are administered to the
mammal, to treat disorders related to androgen receptor function,
or which can be improved by the addition of additional androgen,
such as osteoporosis, periodontal disease, bone fracture, bone
damage following bone reconstructive surgery, sarcopenia, frailty,
aging skin, male hypogonadism, post-menopausal symptoms in women,
atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic
anemia and other hematopoietic disorders, pancreatic cancer,
inflammatory arthritis and joint repair.
It is generally preferable to administer compounds of the present
invention in their enantiomerically pure form. Racemic mixtures can
be separated into their individual enantiomers by any of a number
of conventional methods. These include chiral chromatography,
derivatization with a chiral auxiliary followed by separation by
chromatography or crystallization, and fractional crystallization
of diastereomeric salts.
As used herein, a compound of the present invention which functions
as an "agonist" of the androgen receptor can bind to the androgen
receptor and initiate a physiological or a pharmacological response
characteristic of that receptor. The term "tissue-selective
androgen receptor modulator" refers to an androgen receptor ligand
that mimics the action of a natural ligand in some tissues but not
in others. A "partial agonist" is an agonist which is unable to
induce maximal activation of the receptor population, regardless of
the amount of compound applied. A "full agonist" induces full
activation of the androgen receptor population at a given
concentration. A compound of the present invention which functions
as an "antagonist" of the androgen receptor can bind to the
androgen receptor and block or inhibit the androgen-associated
responses normally induced by a natural androgen receptor
ligand.
The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids. Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic salts, manganous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, lithium,
magnesium, potassium, and sodium salts. Salts derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines,
and basic ion exchange resins, such as arginine, betaine, caffeine,
choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabarine, isopropylarine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobrornine, triethylamine,
trimethylarine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be
prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,
isethionic, lactic, maleic, malic, mandelic, methanesulfonic,
malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic,
succinic, sulfuric, tartaric, p-toluenesulfonic acid,
trifluoroacetic acid, and the like. Particularly preferred are
citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric,
sulfuric, and tartaric acids.
The term "therapeutically effective amount" means the amount the
compound of structural formula I that will elicit the biological or
medical response of a tissue, system, animal or human that is being
sought by the researcher, veterinarian, medical doctor or other
clinician.
The term "composition" as used herein is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the
specified amounts.
By "pharmaceutically acceptable" it is meant that the carrier,
diluent or excipient must be compatible with the other ingredients
of the formulation and not be deleterious to the recipient
thereof.
The terms "administration of a compound" and "administering a
compound" should be understood to mean providing a compound of the
invention or a prodrug of a compound of the invention to the
individual in need of treatment.
The administration of the compound of structural formula I in order
to practice the present methods of therapy is carried out by
administering an effective amount of the compound of structural
formula I to the patient in need of such treatment or prophylaxis.
The need for a prophylactic administration according to the methods
of the present invention is determined via the use of well-known
risk factors. The effective amount of an individual compound is
determined, in the final analysis, by the physician in charge of
the case, but depends on factors such as the exact disease to be
treated, the severity of the disease and other diseases or
conditions from which the patient suffers, the chosen route of
administration, other drugs and treatments which the patient may
concomitantly require, and other factors in the physician's
judgment.
Generally, the daily dosage of the compound of structural formula I
may be varied over a wide range from 0.01 to 1000 mg per adult
human per day. Most preferably, dosages range from 0.1 to 200
mg/day. For oral administration, the compositions are preferably
provided in the form of tablets containing 0.01 to 1000 mg,
particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0,
15.0, 25.0, 50.0, 75, 100, 125, 150, 175, 180, 200, 225, and 500
milligrams of the active ingredient for the symptomatic adjustment
of the dosage to the patient to be treated.
The dose may be administered in a single daily dose or the total
daily dosage may be administered in divided doses of two, three or
four times daily. Furthermore, based on the properties of the
individual compound selected for administration, the dose may be
administered less frequently, e.g., weekly, twice weekly, monthly,
etc. The unit dosage will, of course, be correspondingly larger for
the less frequent administration.
When administered via intranasal routes, transdermal routes, by
rectal or vaginal suppositories, or through an intravenous
solution, the dosage administration will, of course, be continuous
rather than intermittent throughout the dosage regimen.
Exemplifying the invention is a pharmaceutical composition
comprising any of the compounds described above and a
pharmaceutically acceptable carrier. Also exemplifying the
invention is a pharmaceutical composition made by combining any of
the compounds described above and a pharmaceutically acceptable
carrier. An illustration of the invention is a process for making a
pharmaceutical composition comprising combining any of the
compounds described above and a pharmaceutically acceptable
carrier.
Formulations of the tissue-selective androgen receptor modulator
employed in the present method for medical use comprise the
compound of structural formula I together with an acceptable
carrier thereof and optionally other therapeutically active
ingredients. The carrier must be pharmaceutically acceptable in the
sense of being compatible with the other ingredients of the
formulation and not being deleterious to the recipient subject of
the formulation.
The present invention, therefore, further provides a pharmaceutical
formulation comprising the compound of structural formula I
together with a pharmaceutically acceptable carrier thereof.
The formulations include those suitable for oral, rectal,
intravaginal, topical or parenteral (including subcutaneous,
intramuscular and intravenous administration). Preferred
formulations are those suitable for oral administration.
The formulations may be presented in a unit dosage form and may be
prepared by any of the methods known in the art of pharmacy. All
methods include the step of bringing the active compound in
association with a carrier which constitutes one or more
ingredients. In general, the formulations are prepared by uniformly
and intimately bringing the active compound in association with a
liquid carrier, a waxy solid carrier or a finely divided solid
carrier, and then, if needed, shaping the product into the desired
dosage form.
Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets, tablets or lozenges, each containing a predetermined
amount of the active compound; as a powder or granules; or a
suspension or solution in an aqueous liquid or non-aqueous liquid,
e.g., a syrup, an elixir, or an emulsion.
A tablet may be made by compression or molding, optionally with one
or more accessory ingredients. Compressed tablets may be prepared
by compressing in a suitable machine the active compound in a free
flowing form, e.g., a powder or granules, optionally mixed with
accessory ingredients, e.g., binders, lubricants, inert diluents,
disintegrating agents or coloring agents. Molded tablets may be
made by molding in a suitable machine a mixture of the active
compound, preferably in powdered form, with a suitable carrier.
Suitable binders include, without limitation, starch, gelatin,
natural sugars such as glucose or beta-lactose, corn sweeteners,
natural and synthetic gums such as acacia, tragacanth or sodium
alginate, carboxymethyl-cellulose, polyethylene glycol, waxes and
the like. Lubricants used in these dosage forms include, without
limitation, sodium oleate, sodium stearate, magnesium stearate,
sodium benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like.
Oral liquid forms, such as syrups or suspensions in suitably
flavored suspending or dispersing agents such as the synthetic and
natural gums, for example, tragacanth, acacia, methyl cellulose and
the like, may be made by adding the active compound to the solution
or suspension. Additional dispersing agents which may be employed
include glycerin and the like.
Formulations for vaginal or rectal administration may be presented
as a suppository with a conventional carrier, i.e., a base that is
nontoxic and nonirritating to mucous membranes, compatible with the
compound of structural formula I, and is stable in storage and does
not bind or interfere with the release of the compound of
structural formula I. Suitable bases include: cocoa butter
(theobroma oil), polyethylene glycols (such as carbowax and
polyglycols), glycol-surfactant combinations, polyoxyl 40 stearate,
polyoxyethylene sorbitan fatty acid esters (such as Tween, Myrj,
and Arlacel), glycerinated gelatin, and hydrogenated vegetable
oils. When glycerinated gelatin suppositories are used, a
preservative such as methylparaben or propylparaben may be
employed.
Topical preparations containing the active drug component can be
admixed with a variety of carrier materials well known in the art,
such as, e.g., alcohols, aloe vera gel, allantoin, glycerine,
vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and
the like, to form, e.g., alcoholic solutions, topical cleansers,
cleansing creams, skin gels, skin lotions, and shampoos in cream or
gel formulations.
The compounds of the present invention can also be administered in
the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles and multilamellar vesicles.
Liposomes can be formed from a variety of phospholipids, such as
cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use
of monoclonal antibodies as individual carriers to which the
compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinyl-pyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide
polylysine substituted with palmitoyl residues. Furthermore, the
compounds of the present invention may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross-inked linked or
amphipathic block copolymers of hydrogels.
Formulations suitable for parenteral administration include
formulations that comprise a sterile aqueous preparation of the
active compound which is preferably isotonic with the blood of the
recipient. Such formulations suitably comprise a solution or
suspension of a compound that is isotonic with the blood of the
recipient subject. Such formulations may contain distilled water,
5% dextrose in distilled water or saline and the active compound.
Often it is useful to employ a pharmaceutically and
pharmacologically acceptable acid addition salt of the active
compound that has appropriate solubility for the solvents employed.
Useful formulations also comprise concentrated solutions or solids
comprising the active compound which on dilution with an
appropriate solvent give a solution suitable for parenteral
administration.
The compounds of the present invention may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates, and cross-linked or
amphipathic block copolymers of hydrogels.
The pharmaceutical composition and method of the present invention
may further comprise other therapeutically active compounds usually
applied in the treatment and prevention of the above mentioned
conditions, including osteoporosis, periodontal disease, bone
fracture, bone damage following bone reconstructive surgery,
sarcopenia, frailty, aging skin, male hypogonadism, post-menopausal
symptoms in women, atherosclerosis, hypercholesterolemia,
hyperlipidemia, aplastic anemia and other hematopoietic disorders,
pancreatic cancer, inflammatory arthintis, and joint repair.
For the treatment and prevention of osteoporosis, the compounds of
the present invention may be administered in combination with a
bone-strengthening agent selected from antiresorptive agents,
osteoanabolic agents, and other agents beneficial for the skeleton
through mechanisms which are not precisely defined, such as calcium
supplements, flavonoids, and vitamin D analogs. The conditions of
periodontal disease, bone fracture, and bone damage following bone
reconstructive surgery may also benefit from these combined
treatments. For example, the compounds of the instant invention may
be effectively administered in combination with effective amounts
of other agents such as estrogens, bisphosphonates, SERMs,
cathepsin K inhibitors, .alpha.v.beta.3 integrin receptor
antagonists, vacuolar ATPase inhibitors, the polypeptide
osteoprotegerin, antagonists of VEGF, thiazolidinediones,
calcitonin, protein kinase inhibitors, parathyroid hormone (PTH and
analogs, calcium receptor antagonists, growth hormone
secretagogues, growth hormone releasing hormone, insulin-like
growth factor, bone morphogenetic protein (BMP), inhibitors of BMP
antagonism, prostaglandin derivatives, fibroblast growth factors,
vitamin D and derivatives thereof, vitamin K and derivatives
thereof, soy isoflavones, calcium salts, and fluoride salts. The
conditions of periodontal disease, bone fracture, and bone damage
following bone reconstructive surgery may also benefit from these
combined treatments. In one embodiment of the present invention, a
compound of the instant invention may be effectively administered
in combination with an effective amount of a bone-strengthening
agent selected from the group consisting of estrogen or an estrogen
derivative, alone or in combination with a progestin or progestin
derivative; a bisphosphonate; an antiestrogen or a selective
estrogen receptor modulator; an .alpha.v.beta.3 integrin receptor
antagonist; a cathepsin K inhibitor; an osteoclast vacuolar ATPase
inhibitor; calcitonin; and osteoprotegerin.
In the treatment of osteoporosis, the activity of the compounds of
the present invention are distinct from that of the anti-resorptive
agents: estrogens, bisphosphonates, SERMs, calcitonin, cathepsin K
inhibitors, vacuolar ATPase inhibitors, agents interfering with the
RANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any other
inhibitors of osteoclast generation or osteoclast activation.
Rather than inhibiting bone resorption, the compounds of structural
formula I stimulate bone formation, acting preferentially on
cortical bone, which is responsible for a significant part of bone
strength. The thickening of cortical bone substantially contributes
to a reduction in fracture risk, especially fractures of the hip.
The combination of the tissue-selective androgen receptor
modulators of structural formula I with anti-resorptive agents such
as estrogen, bisphosphonates, antiestrogens, SERMs, calcitonin,
.alpha.v.beta.3 integrin receptor antagonists, HMG-CoA reductase
inhibitors, vacuolar ATPase inhibitors, and cathepsin K inhibitors
is particularly useful because of the complementarity of the bone
anabolic and antiresorptive actions.
Bone antiresportive agents are those agents which are known in the
art to inhibit the resorption of bone and include, for example,
estrogen and estrogen derivatives which include steroidal compounds
having estrogenic activity such as, for example,
17.beta.-estradiol, estrone, conjugated estrogen (PREMARIN.RTM.),
equine estrogen, 17.beta.-ethynyl estradiol, and the like. The
estrogen or estrogen derivative may be employed alone or in
combination with a progestin or progestin derivative. Nonlimiting
examples of progestin derivatives are norethindrone and
medroxy-progesterone acetate.
Bisphosphonates are also bone anti-resorptive agents.
Bisphosphonate compounds which may also be employed in combination
with a compound of structural formula I of the present invention
include: (a) alendronic acid:
(4-amino-1-hydroxybutylidene)-bis-phosphonic acid; (b) alendronate
(also known as alendronate sodium or monosodium trihydrate):
(4-amino-1-hydroxybutylidene)-bis-phosphonate monosodium trihydrate
(alendronic acid and alendronate are described in U.S. Pat. No.
4,922,007, to Kieczykowski et al., issued May 1, 1990, and U.S.
Pat. No. 5,019,651, to Kieczykowski, issued May 28, 1991, both of
which are incorporated by reference herein in their entirety); (c)
[cycloheptylamino-methylene]-bis-phosphonate (incadronate), which
is described in U.S. Pat. No. 4,970,335, to Isomura et al., issued
Nov. 13, 1990, which is incorporated by reference herein in its
entirety; (d) (dichloromethylene)-bis-phosphonic acid (clodronic
acid) and the disodium salt (clodronate), which are described in
Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967),
both of which are incorporated by reference herein in their
entirety; (e)
[1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bis-phosphonate
(EB-1053); (f) (1-hydroxyethylidene)-bis-phosphonate (etidronate);
(g) [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate
(ibandronate), which is described in U.S. Pat. No. 4,927,814,
issued May 22, 1990, which is incorporated by reference herein in
its entirety; (h) (6-amino-1hydroxyhexylidene)-bis-phosphonate
(neridronate); (i)
[3-(dimethylamino)-1-hydroxypropylidene]-bis-phosphonate
(olpadronate); (j) (3-amino-1-hydroxypropylidene)-bis-phosphonate
(pamidronate); (k) [2-(2-pyridinyl)ethylidene]-bis-phosphonate
(piridronate), which is described in U.S. Pat. No. 4,761,406, which
is incorporated by reference in its entirety; (l)
[1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate
(risedronate); (m)
{[(4-chlorophenyl)thio]methylene}-bis-phosphonate (tiludronate),
which is described in U.S. Pat. No. 4,876,248, to Breliere et al.,
Oct. 24, 1989, which is incorporated by reference herein in its
entirety; (n)
[1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bis-phosphonate
(zoledronate); and (o)
[1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bis-phosphona-
te (minodronate).
Preferred are bisphosphonates selected from the group consisting of
alendronate, clodronate, EB-1053, etidronate, ibandronate,
incadronate, minodronate, neridronate, olpadronate, pamidronate,
piridronate, risedronate, tiludronate, and zoledronate, and
pharmaceutically acceptable salts thereof, and mixtures
thereof.
More preferred is alendronate, pharmaceutically acceptable salts
thereof, and mixtures thereof.
Most preferred is alendronate monosodium trihydrate.
Still further, antiestrogenic compounds such as raloxifene (see,
e.g., U.S. Pat. No. 5,393,763), clomiphene, zuclomiphene,
enclomiphene, nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25,
U-11,555A, U-100A, and salts thereof, and the like (see, e.g., U.S.
Pat. Nos. 4,729,999 and 4,894,373) may be employed in combination
with a compound of structural formula I in the methods and
compositions of the present invention. These agents are also known
as SERMs, or selective estrogen receptor modulators, agents known
in the art to prevent bone loss by inhibiting bone resorption via
pathways believed to be similar to those of estrogens. These agents
may be used in combination with the compounds of the present
invention to beneficially treat bone disorders including
osteoporosis. Such agents include, for example, tamoxifen,
raloxifene, lasofoxifene, toremifene, azorxifene, EM-800, EM-652,
TSE 424, clomiphene, droloxifene, idoxifene, and levormeloxifene
[Goldstein, et al., "A pharmacological review of selective
oestrogen receptor modulators," Human Reproduction Update, 6:
212-224 (2000), and Lufkin, et al., "The role of selective estrogen
receptor modulators in the prevention and treatment of
osteoporosis," Rheumatic Disease Clinics of North America, 27:
163-185 (2001)]. SERMs are also discussed in "Targeting the
Estrogen Receptor with SERMs," Ann. Rep. Med. Chem. 36: 149-158
(2001).
.alpha.v.beta.3 Integrin receptor antagonists suppress bone
resorption and may be employed in combination with the tissue
selective androgen receptor modulators of structural formula I for
the treatment of bone disorders including osteoporosis. Peptidyl as
well as peptidomnimetic antagonists of the .alpha.v.beta.3 integrin
receptor have been described both in the scientific and patent
literature. For example, reference is made to W. J. Hoekstra and B.
L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) and references cited
therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO
98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO
98/30542; WO 99/15506; WO 99/15507; WO 00/03973; EP 853084; EP
854140; EP 854145; U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754;
5,741,796; 5,780,426; 5,929,120; 5,952,341; 6,017,925; and
6,048,861. Evidence of the ability of .alpha.v.beta.3 integrin
receptor antagonists to prevent bone resorption in vitro and in
vivo has been presented (see V. W. Engleman et al., "A
Peptidomimetic Antagonist of the .alpha.v.beta.3 Integrin Inhibits
Bone Resorption In Vitro and Prevents Osteoporosis In Vivo," J.
Clin. Invest. 99: 2284-2292 (1997); S. B. Rodan et al., "A High
Affinity Non-Peptide .alpha.v.beta.3 Ligand Inhibits Osteoclast
Activity In Vitro and In Vivo," J. Bone Miner. Res. 11: S289
(1996); J. F. Gourvest et al., "Prevention of OVX-Induced Bone Loss
With a Non-peptidic Ligand of the .alpha.v.beta.3 Vitronectin
Receptor," Bone 23: S612 (1998); M. W. Lark et al., "An Orally
Active Vitronectin Receptor .alpha.v.beta.3 Antagonist Prevents
Bone Resorption In Vitro and In Vivo in the Ovariectomized Rat,"
Bone 23: S219 (1998)). Other .alpha.v.beta.3 antagonists are
described in R. M. Keenan et al., "Discovery of Potent Nonpeptide
Vitronectin Receptor (.alpha.v.beta.3) Antagonists," J. Med. Chem.
40: 2289-2292 (1997); R. M. Keenan et al., "Benzimidazole
Derivatives As Arginine Mimetics in 1,4-Benzodiazepine Nonpeptide
Vitronectin Receptor (.alpha.v.beta.3) Antagonists," Bioorg. Med.
Chem. Lett. 8: 3165-3170 (1998); and R. M. Keenan et al.,
"Discovery of an Imidazopyridine-Containing 1,4-Benzodiazepine
Nonpeptide Vitronectin Receptor (.alpha.v.beta.3) Antagonist With
Efficacy in a Restenosis Model," Bioorg. Med. Chem. Lett. 8:
3171-3176 (1998). Still other benzazepine, benzodiazepine and
benzocycloheptene .alpha.v.beta.3 integrin receptor antagonists are
described in the following patent publications: WO 96/00574, WO
96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO
97/24124, WO 98/14192, WO 98/15278, WO 99/05107, WO 99/06049, WO
99/15170, WO 99/15178, WO 99/15506, and U.S. Pat. No. 6,159,964,
and WO 97/34865. .alpha.v.beta.3 integrin receptor antagonists
having dibenzocycloheptene, dibenzocycloheptane and dibenzoxazepine
scaffolds have been described in WO 97/01540, WO 98/30542, WO
99/11626, WO 99/15508, WO 00/33838, U.S. Pat. Nos. 6,008,213, and
6,069,158. Other osteoclast integrin receptor antagonists
incorporating backbone conformational ring constraints have been
described in the patent literature. Published patent applications
or issued patents disclosing antagonists having a phenyl constraint
include WO 98/00395, WO 99/32457, WO 99/37621, WO 99/44994, WO
99/45927, WO 99/52872, WO 99/52879, WO 99/52896, WO 00/06169, EP 0
820,988, EP 0 820,991, U.S. Pat. Nos. 5,741,796; 5,773,644;
5,773,646; 5,843,906; 5,852,210; 5,929,120; 5,952,381; 6,028,223;
and 6,040,311. Published patent applications or issued patents
disclosing antagonists having a monocyclic ring constraint include
WO 99/26945, WO 99/30709, WO 99/30713, WO 99/31099, WO 99/59992, WO
00/00486, WO 00/09503, EP 0 796,855, EP 0 928,790, EP 0 928,793,
U.S. Pat. Nos. 5,710,159; 5,723,480; 5,981,546; 6,017,926; and
6,066,648. Published patent applications or issued patents
disclosing antagonists having a bicyclic ring constraint include WO
98/23608, WO 98/35949, WO 99/33798, EP 0 853,084, U.S. Pat. Nos.
5,760,028; 5,919,792; and 5,925,655. Reference is also made to the
following reviews for additional scientific and patent literature
that concern alpha v integrin antagonists: M. E. Duggan, et al.,
"Ligands to the integrin receptor .alpha.v.beta.3, Exp. Opin. Ther.
Patents, 10: 1367-1383 (2000); M. Gowen, et al., "Emerging
therapies for osteoporosis," Emerging Drugs, 5: 1-43 (2000); J. S.
Kerr, et al., "Small molecule .alpha.v integrin antagonists: novel
anticancer agents," Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000);
and W. H. Miller, et al., "Identification and in vivo efficacy of
small-molecule antagonists of integrin .alpha.v.beta.3 (the
vitronectin receptor)," Drug Discovers Today, 5: 397-408
(2000).
Cathepsin K, formerly known as cathepsin O2, is a cysteine protease
published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,
1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of
which are incorporated by reference herein in their entirety.
Cysteine proteases, specifically cathepsins, are linked to a number
of disease conditions, such as tumor metastasis, inflammation,
arthritis, and bone remodeling. At acidic pH's, cathepsins can
degrade type-I collagen. Cathepsin protease inhibitors can inhibit
osteoclastic bone resorption by inhibiting the degradation of
collagen fibers and are thus useful in the treatment of bone
resorption diseases, such as osteoporosis.
Members of the class of HMG-CoA reductase inhibitors, known as the
"statins," have been found to trigger the growth of new bone,
replacing bone mass lost as a result of osteoporosis (see The Wall
Street Journal, Friday, Dec. 3, 1999, page B1). Therefore, the
statins hold promise for the treatment of bone resorption. Examples
of HMG-CoA reductase inhibitors include statins in their lactonized
or dihydroxy open acid forms and pharmaceutically acceptable salts
and esters thereof, including but not limited to lovastatin (see
U.S. Pat. No. 4,342,767); simvastatin (see U.S. Pat. No.
4,444,784); dihydroxy open-acid simvastatin, particularly the
ammonium or calcium salts thereof; pravastatin, particularly the
sodium salt thereof (see U.S. Pat. No. 4,346,227); fluvastatin,
particularly the sodium salt thereof (see U.S. Pat. No. 5,354,772);
atorvastatin, particularly the calcium salt thereof (see U.S. Pat.
No. 5,273,995); cerivastatin, particularly the sodium salt thereof
(see U.S. Pat. No. 5,177,080), rosuvastatin, also known as ZD-4522
(see U.S. Pat. No. 5,260,440) and pitavastatin, also referred to as
NK-104, itavastatin, or nisvastatin (see PCT international
application publication number WO 97/23200).
Osteoclast vacuolar ATPase inhibitors, also called proton pump
inhibitors, may also be employed together with the tissue selective
androgen receptor modulators of structural formula I. The proton
ATPase which is found on the apical membrane of the osteoclast has
been reported to play a significant role in the bone resorption
process. Therefore, this proton pump represents an attractive
target for the design of inhibitors of bone resorption which are
potentially useful for the treatment and prevention of osteoporosis
and related metabolic diseases [see C. Farina et al., "Selective
inhibitors of the osteoclast vacuolar proton ATPase as novel bone
antiresorptive agents," DDT, 4: 163-172 (1999)].
The angiogenic factor VEGF has been shown to stimulate the
bone-resorbing activity of isolated mature rabbit osteoclasts via
binding to its receptors on osteoclasts [see M. Nakagawa et al.,
"Vascular endothelial growth factor (VEGF) directly enhances
osteoclastic bone resorption and survival of mature osteoclasts,"
FEBS Letters, 473: 161-164 (2000)]. Therefore, the development of
antagonists of VEGF binding to osteoclast receptors, such as
KDR/Flk-1 and Flt-1, may provide yet a further approach to the
treatment or prevention of bone resorption.
Activators of the peroxisome proliferator-activated
receptor-.gamma. (PPAR.gamma.), such as the thiazolidinediones
(TZD's), inhibit osteoclast-like cell formation and bone resorption
in vitro. Results reported by R. Okazaki et al. in Endocrinolog,
140: 5060-5065 (1999) point to a local mechanism on bone marrow
cells as well as a systemic one on glucose metabolism. Nonlimiting
examples of PPAR.gamma. activators include the glitazones, such as
troglitazone, pioglitazone, rosiglitazone, and BRL 49653.
Calcitonin may also be employed together with the tissue selective
androgen receptor modulator of structural formula I. Calcitonin is
preferentially employed as salmon nasal spray (Azra et al.,
Calcitonin. 1996. In: J. P. Bilezikian, et al., Ed., Principles of
Bone Biology, San Diego: Academic Press; and Silverman,
"Calcitonin," Rheumatic Disease Clinics of North America, 27:
187-196, 2001)
Protein kinase inhibitors may also be employed together with the
tissue selective androgen receptor modulators of structural formula
I. Kinase inhibitors include those disclosed in WO 01/17562 and are
in one embodiment selected from inhibitors of P-38. Specific
embodiments of P-38 inhibitors useful in the present invention
include SB 203580 [Badger et al., "Pharmacological profile of SB
203580, a selective inhibitor of cytokine suppressive binding
protein/p38 kinase, in animal models of arthritis, bone resorption,
endotoxin shock, and immune function," J. Pharmacol. Exp. Ther.,
279: 1453-1461 (1996)].
Osteoanabolic agents are those agents that are known in the art to
build bone by increasing the production of the bone protein matrix.
Such osteoanabolic agents include, for example, the various forms
of parathyroid hormone (PTH) such as naturally occurring PTH
(1-84), PTH (1-34), analogs thereof, native or with substitutions
and particularly parathyroid hormone subcutaneous injection. PTH
has been found to increase the activity of osteoblasts, the cells
that form bone, thereby promoting the synthesis of new bone (Modern
Drug Discovery, Vol. 3, No. 8, 2000). In studies reported at the
First World Congress on Osteoporosis held in Chicago in June 2000,
women in combined PTH-estrogen therapy exhibited a 12.8% increase
in spinal bone mass and a 4.4% increase in total hip mass. Another
study presented at the same meeting showed that PTH could increase
bone size as well as density. A clinical trial of the effect of the
human parathyroid hormone 1-34 fragment [hPTH(1-34)] on
postmenopausal osteoporotic women resulted in .gtoreq.65% reduction
in spine fractures and a 54% reduction in nonvertebral fractures,
after a median of 22 months of treatment [see J. M. Hock, Bone, 27:
467-469 (2000) and S. Mohan, et al., Bone, 27: 471-478 (2000), and
references cited therein]. Thus, PTH and fragments thereof, such as
hPTH(1-34), may prove to be efficacious in the treatment of
osteoporosis alone or in combination with other agents, such as the
tissue selective androgen receptor modulators of the present
invention. An injectable recombinant form of human PTH, Forteo
(teriparatide), has received regulatory approval in the U.S. for
the treatment of osteoporosis.
Also useful in combination with the SARMs of the present invention
are calcium receptor antagonists which induce the secretion of PTH
as described by Gowen et al., in "Antagonizing the parathyroid
calcium receptor stimulates parathyroid hormone secretion and bone
formation in osteopenic rats," J. Clin. Invest. 105: 1595-604
(2000).
Growth hormone secretagogues, growth hormone, growth hormone
releasing hormone and the like are also osteoanabolic agents which
may be employed with the compounds according to structural formula
I for the treatment of osteoporosis. Representative growth hormone
secretagogues are disclosed in U.S. Pat. No. 3,239,345; U.S. Pat.
No. 4,036,979; U.S. Pat. No. 4,411,890; U.S. Pat. No. 5,206,235;
U.S. Pat. No. 5,283,241; U.S. Pat. No. 5,284,841; U.S. Pat. No.
5,310,737; U.S. Pat. No. 5,317,017; U.S. Pat. No. 5,374,721; U.S.
Pat. No. 5,430,144; U.S. Pat. No. 5,434,261; U.S. Pat. No.
5,438,136; U.S. Pat. No. 5,494,919; U.S. Pat. No. 5,494,920; U.S.
Pat. No. 5,492,916; U.S. Pat. No. 5,536,716; EPO Patent Pub. No.
0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO
94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO
94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO
94/19367; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO
95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO
95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO
95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO
95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO
95/34311; PCT Patent Pub. No. WO 96/02530; Science, 260, 1640-1643
(Jun. 11, 1993); Ann. Rep. Med. Chem., 28: 177-186 (1993); Bioorg.
Med. Chem. Lett., 4: 2709-2714 (1994); and Proc. Natl. Acad. Sci.
USA, 92: 7001-7005 (1995).
Insulin-like growth factor (IGF) may also be employed together with
the tissue selective androgen receptor modulators of structural
formula I. Insulin-like growth factors may be selected from
Insulin-like Growth Factor I, alone or in combination with IGF
binding protein 3 and IGF II [See Johannson and Rosen, "The IGFs as
potential therapy for metabolic bone diseases," 1996, In:
Bilezikian, et al., Ed., Principles of Bone Biology, San Diego:
Academic Press; and Ghiron et al., "Effects of recombinant
insulin-like growth factor-I and growth hormone on bone turnover in
elderly women," J. Bone Miner. Res. 10: 1844-1852 (1995)].
Bone morphogenetic protein (BMP) may also be employed together with
the tissue selective androgen receptor modulators of structural
formula I. Bone morphogenetic protein includes BMP 2, 3, 5, 6, 7,
as well as related molecules TGF beta and GDF 5 [Rosen et al.,
"Bone morphogenetic proteins," 1996. In: J. P. Bilezikian, et al.,
Ed., Principles of Bone Biology, San Diego: Academic Press; and
Wang E A, "Bone morphogenetic proteins (BMPs): therapeutic
potential in healing bony defects," Trends Biotechnol., 11: 379-383
(1993)].
Inhibitors of BMP antagonism may also be employed together with the
tissue selective androgen receptor modulators of structural formula
I. BMP antagonist inhibitors are in one embodiment selected from
inhibitors of the BMP antagonists SOST, noggin, chordin, gremlin,
and dan [Massague and Chen, "Controlling TGF-beta signaling," Genes
Dev., 14: 627-644, 2000; Aspenberg et al., "The bone morphogenetic
proteins antagonist Noggin inhibits membranous ossification," J.
Bone Miner. Res. 16: 497-500, 2001; Brunkow et al., "Bone dysplasia
sclerosteosis results from loss of the SOST gene product, a novel
cystine knot-containing protein," Am. J. Hum. Genet. 68: 577-89
(2001)].
The tissue-selective androgen receptor modulators of the present
invention may also be combined with the polypeptide osteoprotegerin
for the treatment of conditions associated with bone loss, such as
osteoporosis. Preferably osteoprotegerin is mammalian
osteoprotegerin and more preferably human osteoprotegerin. The
polypeptide osteoprotegerin, a member ot the tumor necrosis factor
receptor superfamily, is useful to treat bone diseases
characterized by increased bone loss, such as osteoporosis.
Reference is made to U.S. Pat. No. 6,288,032, which is incorporated
by reference herein in its entirety.
Prostaglandin derivatives may also be employed together with the
tissue selective androgen receptor modulators of structural formula
I. Prostaglandin derivatives are in one embodiment selected from
agonists of prostaglandin receptor EP1, EP2, EP4, FP and IP or a
derivative thereof [Pilbeam et al., "Prostaglandins and bone
metabolism," 1996. In: Bilezikian, et al. Ed. Principles of Bone
Biology, San Diego: Academic Press; Weinreb et al., "Expression of
the prostaglandin E(2) (PGE(2)) receptor subtype EP(4) and its
regulation by PGE(2) in osteoblastic cell lines and adult rat bone
tissue," Bone, 28: 275-281 (2001)].
Fibroblast growth factors may also be employed together with the
tissue selective androgen receptor modulators of structural formula
I. Fibroblast growth factors include aFGF, bFGF and related
peptides with FGF activity [Hurley Florkiewicz, "Fibroblast growth
factor and vascular endothelial growth factor families," 1996. In:
J. P. Bilezikian, et al., Ed. Principles of Bone Biology, San
Diego: Academic Press].
In addition to bone resorption inhibitors and osteoanabolic agents,
there are also other agents known to be beneficial for the skeleton
through mechanisms which are not precisely defined. These agents
may also be favorably combined with the tissue selective androgen
receptor modulators of structural formula I.
Vitamin D and vitamin D derivatives may also be employed together
with the tissue selective androgen receptor modulator of structural
formula I. Vitamin D and vitamin D derivatives include natural
vitamin D, 25-OH-vitamin D3, 1.alpha.,25(OH).sub.2 vitamin D3,
1.alpha.-OH-vitamin D3, 1.alpha.-OH-vitamin D2, dihydrotachysterol,
26,27-F6-1.alpha.,25(OH).sub.2 vitamin D3,
19-nor-1.alpha.,25(OH).sub.2 vitamin D3, 22-oxacalcitriol,
calcipotriol, 1.alpha.,25(OH).sub.2-16-ene-23-yne-vitamin D3 (Ro
23-7553), EB1089, 20-epi-1.alpha.,25(OH).sub.2 vitamin D3, KH1060,
ED71, 1.alpha.,24(S)-(OH).sub.2 vitamin D3,
1.alpha.,24(R)-(OH).sub.2 vitamin D3 [See, Jones G.,
"Pharmacological mechanisms of therapeutics: vitamin D and
analogs," 1996. In: J. P. Bilezikian, et. al. Ed. Principles of
Bone Biology, San Diego: Academic Press].
Vitamin K and vitamin K derivatives may also be employed together
with the tissue selective androgen receptor modulators of
structural formula I. Vitamin K and vitamin K derivatives include
menatetrenone (vitamin K2) [see Shiraki et al., "Vitamin K2
(menatetrenone) effectively prevents fractures and sustains lumbar
bone mineral density in osteoporosis," J. Bone Miner. Res., 15:
515-521 (2000)].
Soy isoflavones, including ipriflavone, may be employed together
with the tissue selective androgen receptor modulators of
structural formula I.
Fluoride salts, including sodium fluoride (NaF) and monosodium
fluorophosphate (MFP), may also be employed together with the
tissue selective androgen receptor modulators of structural formula
I, Dietary calcium supplements may also be employed together with
the tissue selective androgen receptor modulators of structural
formula I. Dietary calcium supplements include calcium carbonate,
calcium citrate, and natural calcium salts (Heaney. Calcium. 1996.
In: J. P. Bilezikian, et al., Ed., Principles of Bone Biology, San
Diego: Academic Press).
Daily dosage ranges for bone resorption inhibitors, osteoanabolic
agents and other agents which may be used to benefit the skeleton
when used in combination with the compounds of structural formula I
are those which are known in the art. In such combinations,
generally the daily dosage range for the tissue selective androgen
receptor modulator of structural formula I is 0.01 to 1000 mg per
adult human per day, more preferably from 0.1 to 200 mg/day.
However, adjustments to decrease the dose of each agent may be made
due to the increased efficacy of the combined agent.
In particular, when a bisphosphonate is employed, dosages of 2.5 to
100 mg/day (measured as the free bisphosphonic acid) are
appropriate for treatment, more preferably 5 to 20 mg/day,
especially about 10 mg/day. Prophylactically, doses of about 2.5 to
about 10 mg/day and especially about 5 mg/day should be employed.
For reduction in side-effects, it may be desirable to administer
the combination of the compound of structural formula I and the
bisphosphonate once a week. For once weekly administration, doses
of about 15 mg to 700 mg per week of bisphosphonate and 0.07 to
7000 mg of the compound of structural formula I may be employed,
either separately, or in a combined dosage form. The compound of
structural formula I may be favorably administered in a
controlled-release delivery device, particularly for once weekly
administration.
For the treatment of atherosclerosis, hypercholesterolemia, and
hyperlipidemia, the compounds of structural formula I may be
effectively administered in combination with one or more additional
active agents. The additional active agent or agents can be
lipid-altering compounds such as HMG-CoA reductase inhibitors, or
agents having other pharmaceutical activities, or agents that have
both lipid-altering effects and other pharmaceutical activities.
Examples of HMG-CoA reductase inhibitors include statins in their
lactonized or dihydroxy open acid forms and pharmaceutically
acceptable salts and esters thereof, including but not limited to
lovastatin (see U.S. Pat. No. 4,342,767); simvastatin (see U.S.
Pat. No. 4,444,784); dihydroxy open-acid simvastatin, particularly
the amnmonium or calcium salts thereof; pravastatin, particularly
the sodium salt thereof (see U.S. Pat. No. 4,346,227); fluvastatin,
particularly the sodium salt thereof (see U.S. Pat. No. 5,354,772);
atorvastatin, particularly the calcium salt thereof (see U.S. Pat.
No. 5,273,995); cerivastatin, particularly the sodium salt thereof
(see U.S. Pat. No. 5,177,080), and nisvastatin, also referred to as
NK-104 (see PCT international application publication number WO
97/23200). Additional active agents which may be employed in
combination with a compound of structural formula I include, but
are not limited to, HMG-CoA synthase inhibitors; squalene epoxidase
inhibitors; squalene synthetase inhibitors (also known as squalene
synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase
(ACAT) inhibitors including selective inhibitors of ACAT-1 or
ACAT-2 as well as dual inhibitors of ACAT-1 and -2; microsomal
triglyceride transfer protein (MTP) inhibitors; probucol; niacin;
cholesterol absorption inhibitors, such as SCH-58235, also known as
ezetimibe and
1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]4(S)-(4-h-
ydroxyphenyl)-2-azetidinone, which is described in U.S. Pat. Nos.
5,767,115 and 5,846,966; bile acid sequestrants; LDL (low density
lipoprotein) receptor inducers; platelet aggregation inhibitors,
for example glycoprotein IIb/IIIa fibrinogen receptor antagonists
and aspirin; human peroxisome proliferator activated receptor gamma
(PPAR.gamma.) agonists, including the compounds commonly referred
to as glitazones, for example troglitazone, pioglitazone and
rosiglitazone and, including those compounds included within the
structural class known as thiazolidinediones as well as those
PPAR.gamma. agonists outside the thiazohdinedione structural class;
PPAR.alpha. agonists, such as clofibrate, fenofibrate including
micronized fenofibrate, and gemfibrozil; PPAR dual .alpha./.gamma.
agonists; vitamin B.sub.6 (also known as pyridoxine) and the
pharmaceutically acceptable salts thereof such as the HCl salt;
vitamin B.sub.12 (also known as cyanocobalamin); folic acid or a
pharmaceutically acceptable salt or ester thereof such as the
sodium salt and the methylglucamine salt; anti-oxidant vitamins
such as vitamin C and E and beta carotene; beta-blockers;
angiotensin II antagonists such as losartan; angiotensin converting
enzyme inhibitors, such as enalapril and captopril; calcium channel
blockers, such as nifedipine and diltiazem; endothelin antagonists;
agents such as LXR ligands that enhance ABC1 gene expression;
bisphosphonate compounds, such as alendronate sodium; and
cyclooxygenase-2 inhibitors, such as rofecoxib and celecoxib, as
well as other agents known to be useful in the treatment of these
conditions.
Daily dosage ranges for HMG-CoA reductase inhibitors when used in
combination with the compounds of structural formula I correspond
to those which are known in the art. Similarly, daily dosage ranges
for the HMG-CoA synthase inhibitors; squalene epoxidase inhibitors;
squalene synthetase inhibitors (also known as squalene synthase
inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT)
inhibitors including selective inhibitors of ACAT-1 or ACAT-2 as
well as dual inhibitors of ACAT-1 and -2; microsomal triglyceride
transfer protein (MTP) inhibitors; probucol; niacin; cholesterol
absorption inhibitors including ezetimibe; bile acid sequestrants;
LDL (low density lipoprotein) receptor inducers; platelet
aggregation inhibitors, including glycoprotein IIb/IIIa fibrinogen
receptor antagonists and aspirin; human peroxisome proliferator
activated receptor gamnma (PPAR.gamma.) agonists; PPAR.alpha.
agonists; PPAR dual .alpha./.gamma. agonists; vitamin B.sub.6;
vitamin B.sub.12; folic acid; anti-oxidant vitamins; beta-blockers;
angiotensin II antagonists; angiotensin converting enzyme
inhibitors; calcium channel blockers; endothelin antagonists;
agents such as LXR ligands that enhance ABC1 gene expression;
bisphosphonate compounds; and cyclooxygenase-2 inhibitors also
correspond to those which are known in the art, although due to the
combined action with the compounds of structural formula I, the
dosage may be somewhat lower when administered in combination.
In accordance with the method of the present invention, the
individual components of the combination can be administered
separately at different times during the course of therapy or
concurrently in divided or single combination forms. The instant
invention is therefore to be understood as embracing all such
regimes of simultaneous or alternating treatment and the term
"administering" is to be interpreted accordingly. It will be
understood that the scope of combinations of the compounds of this
invention with other agents useful for treating diseases caused by
androgen deficiency or that can be ameliorated by addition of
androgen.
Preparation of the Compounds of the Invention
The compounds of structural formula I of the present invention can
be prepared according to the procedures of the following Schemes
and Examples, using appropriate materials and are further
exemplified by specific examples provided below.
Compounds of structural formula I can be prepared from a
17.beta.-carboxylic acid intermediate such as 1-1. Intermediate
1-1can be activated such as by conversion into the corresponding
acid chloride 1-1by treatment with a halogenating agent in a
suitable organic solvent, such as thionyl chloride or oxalyl
chloride in the presence of DMF. The derived acid chloride 1-1is
then treated with an appropriately substituted arylamine optionally
in the presence of a suitable base such as N-methylmorpholine and
4-(dimethylamino)-pyridine to afford the compound of structural
formula I, such as 1-1. Reference is made to Harrison and Harrison,
Compendium of Organic Synthetic Methods, Volumes 1-4,
Wiley-Interscience, for a description of methods for the synthesis
of carboxylic acid arylamides.
The preparation of 3-oxoandrost-4-ene-17.beta.-carbonyl chloride
(1-2) is described in U.S. Pat. No. 4,377,584, which is
incorporated by reference herein in its entirety.
##STR00007##
The following examples are provided to further illustrate details
for the preparation and use of the compounds of the present
invention. They are not intended to be limitations on the scope of
the instant invention in any way, and they should not be so
construed. Furthermore, the compounds described in the following
examples are not to be construed as forming the only genus that is
considered as the invention, and any combination of the compounds
or their moieties may itself form a genus. Those skilled in the art
will readily understand that known variations of the conditions and
processes of the following preparative procedures can be used to
prepare these compounds. All temperatures are in degrees Celsius
unless noted otherwise.
EXAMPLE 1
##STR00008##
Step A: 3-oxoandrost-4-ene-17.beta.-carbonyl chloride (1-2)
To a solution of 3-oxoandrost-4-ene-17-beta-carboxylic acid (1-1)
(1.0 g, 3.16 mmol) in 15.8 mL anhydrous CH.sub.2Cl.sub.2 at
0.degree. C. under a nitrogen atmosphere was added 0.010 mL DMF
followed by slow addition of oxalyl chloride (0.330 mL, 3.78 mmol).
The ice bath was then removed and the reaction was stirred at room
temperature for several hours. The mixture was concentrated to a
tan foam which was then dissolved in 10.0 mL of anhydrous
CH.sub.2Cl.sub.2, stored in the freezer, and used as it is in
subsequent reactions.
Step B:
(17.beta.)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carb-
oxamide (1-3a)
To a solution of N-methylmorpholine (0.28 g, 2.8 mmol) and
2-(trifluoromethyl)aniline (0.5 g, 3.1 mmol) in anhydrous
CH.sub.2Cl.sub.2 (3.0 mL) at 0.degree. C. under a nitrogen
atmosphere was added a solution of
3-oxoandrost-4-ene-17.beta.-carbonyl chloride from Step A (2.56
mmol) in anhydrous CH.sub.2Cl.sub.2 (8.1 mL) dropwise. The ice bath
was removed and the mixture stirred at room temperature overnight.
The reaction was then concentrated and the residue was purified by
flash chromatography on silica gel eluting with 0 to 50%
EtOAc-hexanes to afford the desired product as a white solid.
.sup.1H-NMR (CDCl.sub.3): .delta. 8.32 (d, J=8.3 Hz, 1H), 7.60 (d,
J=7.8 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.40 (s, 1H), 7.20 (t, J=7.6
Hz, 1H), 5.75 (s, 1H), 2.47-2.26 (m, 5H), 2.12 (dt, J=12.0, 3.2 Hz,
1H), 2.04 (m, 1H), 1.90 (m, 2H), 1.82-1.57 (m, 4H), 1.53-1.34 (m,
3H), 1.20 (m, 4H), 1.13-0.97 (m, 2H), 0.82 (s, 3H).
Mass spectrum: (M.sup.++H) 460.2487.
Following procedures similar to that described above for Example 1,
the following compounds were prepared:
TABLE-US-00001 ##STR00009## Parent Ion m/z Ex. # X (M + H) 2
3-CF.sub.3 460 3 4-CF.sub.3 460 4 2-OMe 422 5 3-OMe 422 6 4-OMe 422
7 --H 392 8 2-Cl 426 9 3-Cl 426 10 4-Cl 426 11 2-Me 406 12 3-Me 406
13 4-Me 406 14 2-F 410 15 3-F 410 16 4-F 410 17 2-Br 470 18 2-I 518
19 3-OMe, 5-CF.sub.3 490
##STR00010##
EXAMPLE 20
(17.beta.)-N-Methyl-3-oxo-4-(2-trifluoromethylphenyl)-androst-4-ene-17-car-
boxamide (2-2)
To a suspension of NaH (0.009 g, 0.24 mmol) in 1.0 mL anhydrous THF
at 0.degree. C. under N.sub.2 was added
(17.beta.)-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-carboxamide
(2-1) (0.10 g, 0.22 mmol). The mixture was stirred for 30-45 min,
followed by addition of methyl iodide (0.046 g, 0.33 mmol). The ice
bath was removed and the solution was stirred at room temperature
for 45 min. The reaction was quenched with 10% aqueous KHSO.sub.4
solution and extracted with EtOAc. The organic phase was washed
with saturated NaHCO.sub.3 solution and brine and dried with
MgSO.sub.4. After removal of the solvent, the residue was purified
by flash silica gel chromatography (0 to 50% EtOAc-hexanes) to give
the desired product 2-2as a white solid.
MS (M.sup.++H) found 474.2644; calc: 474.25.
##STR00011##
EXAMPLE 21
(17.beta.)-6-Methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-17--
carboxamide (3-4)
Step A:
(17.beta.)-6-(Hydroxymethyl)-3-oxo-N-[4-(trifluoromethyl)phenyl]an-
drost-4-ene-17-carboxamide (3-2, 3-3)
To a suspension of
(17.beta.)-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamid-
e (3-1) (4.13 g, 8.99 mmol) in 24 mL MeOH under N.sub.2 was added
pyrrolidine (1.34 g, 18.87 mmol). The mixture was heated to reflux
for 15-20 min. The mixture was then cooled in an ice bath and
filtered. The solid was dissolved in a mixture of 70 mL EtOH and 35
mL benzene. 37% aqueous formaldehyde (3.48 mL, 46.7 mmol) was
added. The yellowish solution was stirred overnight. The reaction
mixture was then concentrated and purified by flash silica gel
chromatography (0 to 100% EtOAc-hexane) to afford the
6-hydroxymethyl derivative as a mixture of .alpha. and .beta.
epimers (3-2 and 3-3).
Step B:
(17.beta.)-6-Methylene-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-
-ene-17-carboxamide (3-4)
A mixture of
(17.beta.)-6-(hydroxymethyl)-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-
-ene-17-carboxamide (3-2 and 3-3) (0.57 g, 1.2 mmol) was dissolved
in 15 mL 0.6N HCl in dioxane and stirred at rt. After 3 hr, it was
diluted with a large excess of dioxane and stirred overnight. After
removal of the solvent, the residue was dissolved in CHCl.sub.3 and
washed with water, saturated NaHCO.sub.3 solution, and brine, then
dried with MgSO.sub.4 and concentrated. The residue was purified by
flash silica gel chromatography (0 to 50% EtOAc/hexane) to afford
3-4 as the desired product.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.66 (d, 2H), 7.58 (d, 2H), 7.18
(s, 1H), 5.93 (s, 1H), 5.08 (s, 1H), 4.97 (s, 1H), 2.52-2.31 (m,
5H), 2.07 (m, 2H), 1.93-1.67 (m, 6H), 1.53-1.39 (m, 3H), 1.28-1.13
(m, 2H), 1.11 (s, 3H), 0.80 (s, 3H).
EXAMPLE 22
(17.beta.)-6,6-Ethyleno-3-oxo-N-(4-trifluoromethylpheny)-androst-4-ene-17--
carboxamide (3-5)
To a suspension of NaH (0.06 g, 1.4 mmol) in 1.0 mL sieve-dried
DMSO at room temperature under N.sub.2 was added
trimethylsulfoxonium iodide (0.34 g, 1.5 mmol). The mixture was
stirred for 1.5 hr. before a solution of
(17.beta.)-6-methylene-3-oxo-N-[4(trifluoromethyl)phenyl]androst-4-ene-
-17-carboxamide (3-4) (0.24 g, 0.5 mmol) in 3-4 mL DMSO was added
dropwise. After 30 min, the reaction was quenched with 10%
KHSO.sub.4 solution and extracted with CHCl.sub.3. The organic
layer was washed with saturated NaHCO.sub.3 solution and brine,
then dried with MgSO.sub.4 and concentrated. The residue was
purification by preparative HPLC (C.sub.18; 70% MeOH with 5 to 30%
MeCN-water) to give the desired product 3-3as a white solid.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.67 (d, 2H), 7.58 (d, 2H), 7.25
(s, 1H), 5.66 (s, 1H), 2.37 (m, 4H), 2.05 (m, 2H), 1.85 (m, 2H),
1.70 (m, 3H), 1.55 (m, 3H), 1.36 (m, 2H), 1.27 (s, 3H), 1.11 (m,
4H), 0.81 (m, 4H), 0.44 (m, 2H).
MS (M.sup.++H) 486.2567.
##STR00012##
EXAMPLES 23 AND 24
(17.beta.)-6.beta.-Ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-1-
7-carboxamide (4-1) and
(17.beta.)-6.alpha.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene--
17-carboxamide (4-2)
Step A:
(17.beta.)-6-ethyl-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-5-en-
e-17-carboxamide
To a solution of 3.0 M MeMgBr (0.36 mL, 1.09 mmol) in ether under
N.sub.2 was added 2.2 mL Argon-purged, anhydrous THF. The mixture
was cooled to 0.degree. C. CuCl (0.014 g, 0.14 mmol) was added, and
the reaction was stirred for 5 min before adding
(17.beta.)-6-methylene-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-1-
7-carboxamide (3-4) (0.12 g, 0.25 mmol) as a solid. After several
hours the reaction was quenched by dropwise addition of 5.0 mL of
Ar-purged water, then partitioned between CHCl.sub.3 and 10%
KHSO.sub.4 solution. The organic phase was washed with saturated
NaHCO.sub.3 solution and brine, then dried with MgSO.sub.4 and
concentrated. The residue was purified by flash silica gel
chromatography (0 to 30% EtOAc/hexane) and concentrated to yield a
clear, colorless oil, which was further purified by preparative
HPLC (C.sub.18; 70% MeOH with 5 to 30% MeCN-water) to provide the
desired product.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.66 (d, 2H), 7.58 (d, 2H), 7.18
(s, 1H), 3.31 (dd, 1H), 3.04 (dt, 1H), 2.48 (m, 1H), 2.32 (m, 3H),
2.03 (m, 4H), 1.85 (m, 3H), 1.71-1.49 (m, 5H), 1.40 (m, 2H),
1.28-1.05 (m, 5H), 0.91 (t, 3H), 0.80 (s, 3H).
Step B:
(17.beta.)-6.beta.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-
-4-ene-17-carboxamide (4-1) and
(17.beta.)-6.alpha.-ethyl-3-oxo-N-(4-trifluoromethylphenyl)-androst-4-ene-
-17-carboxamide (4-2)
To a solution of
(17.beta.)-6-ethyl-3-oxo-N-[4-(trifluoromethyl)-phenyl]androst-5-ene-17-c-
arboxamide from Step A (0.027 g, 0.055 mmol) in 1.0 mL THF was
added 1.0 N HCl solution (0.5 mL). After 2 hr, the reaction mixture
was concentrated. The residue was purified by preparative HPLC
(C.sub.18; 70% MeOH with 5 to 30% MeCN-water) to yield to afford
the resolved 6-position isomers:
6-alpha isomer (4-2): .sup.1H-NMR (CDCl.sub.3) .delta. 7.68 (d,
2H), 7.57 (d, 2H), 7.30 (s, 1H), 5.80 (s, 1H), 2.45-2.29 (m, 4H),
2.18 (m, 1H), 2.02 (m, 3H), 1.90-1.61 (m, 6H) 1.52-1.23 (m, 5H),
1.19 (s, 3H), 1.16 (m, 1H), 1.02 (dt, 1H), 0.95 (t, 3H), 0.81 (s,
3H), 0.74 (q, 1H).
6-beta isomer (4-1): .sup.1H-NMR (CDCl.sub.3) .delta. 7.65 (d, 2H),
7.58 (d, 2H), 7.10 (s, 1H), 5.74 (s, 1H), 2.54-2.28 (m, 5H), 2.05
(m, 2H), 1.97-1.15 (m), 1.02 (m, 2H), 0.89 (t, 3H), 0.82 (s,
3H).
##STR00013##
EXAMPLE 25
(17.beta.)-7-Methyl-3-oxo-N-(2-trifluoromethylphenyl)-androst-4-ene-17-car-
boxamide (5-3)
Step A:
(17.beta.)-3-oxo-N-[2-(trifluoromethyl)phenyl]androsta-4,6-diene-1-
7-carboxamide (5-2)
A mixture of
(17.beta.)-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamid-
e (2-1) (3.74 g, 8.14 mmol) and p-chloranil (2.40 g, 9.77 mmol) in
t-butanol (40 mL) under N.sub.2 was heated to reflux for 90 min.
The reaction was concentrated and the residue dissolved in EtOAc
and washed with 0.5 N NaOH solution (2.times.60 mL), 10% KHSO.sub.4
solution, and brine. Upon removal of the solvent, the residue was
purified by flash chromatography on silica gel (0 to 35%
EtOAc-hexanes) to afford 5-2 as a brownish foam.
MS (M.sup.++H) 457.8.
Step B:
(17.beta.)-7-methyl-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-5-e-
ne-17-carboxamide (5-3)
To a solution of 3.0 M methylmagnesium bromide (2.35 mmol) in ether
under a stream of N.sub.2 was added 6.0 mL degassed THF. The
solution was cooled to 0.degree. C., then CuCl (0.03 g, 0.300 mmol)
was added. The mixture was stirred for 5 min. A solution of the
compound from Step A (5-2) (0.25 g, 0.55 mmol) in 6.0 mL degassed
THF was added. The reaction was warmed to room temperature
overnight. It was quenched by slow addition of 2.0 mL degassed
water, then diluted with 10% KHSO.sub.4 solution and EtOAc. The
organic phase was washed with 10% KHSO.sub.4 solution, saturated
NaHCO.sub.3 solution, and brine. After removal of the solvent, the
residue was purified by preparative HPLC (C.sub.18; 70% MeOH with 5
to 30% MeCN-water) to provide 5-5.
MS (M.sup.++H) 474.3.
Step C:
(17.beta.)-7-methyl-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-4-e-
ne-17-carboxamide (5-4)
A solution of the compound from Step B (5-3) (0.057 g, 0.12 mmol),
dioxane (0.5 mL) and 1.0 N HCl solution (0.5 mL) was heated to
50.degree. C. for 2 hr. The reaction was then concentrated to yield
the desired product as an 8:1 mixture of epimers at C-7.
MS (M.sup.++H) 474.3.
##STR00014##
EXAMPLES 26 AND 27
(1aR,5aR,7aS,8S,10cR)-5a,7a-Dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide (6-1) and
(1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide (6-2)
To a suspension of NaH (0.25 g, 6.18 mmol) in 7.4 mL DMSO (dried
over molecular sieves) at room temperature under N.sub.2 was added
trimethylsulfoxonium iodide (1.50 g, 6.85 mmol). The mixture was
stirred for 1.5 hr. A solution of
(17.beta.)-3-oxo-N-[2-(trifluoromethyl)phenyl]androsta-4,6-diene-17-carbo-
xamide (5-1) (0.68 g, 1.49 mmol) in 10 mL DMSO was added slowly.
The solution was stirred at room temperature overnight. The
reaction was then quenched by dropwise addition of 10% KHSO.sub.4
solution and extracted with CHCl.sub.3. The organic phase was
washed with 10% KHSO.sub.4 solution, saturated NaHCO.sub.3
solution, and brine, then dried with MgSO.sub.4. After removal of
the solvent, the residue was purified by chiral preparative HPLC
(Chiralpak AD, 85% Hexanes (0.1% diethylamine); 15% 2-propanol) to
yield the desired resolved products 6-6and 6-2. 6-6:
(1aR,5aR,7aS,8S,10cR)-5a,7a-Dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide
MS (M.sup.++H) 472.2443. 6-6:
(1aS,5aR,7aS,8S,10cS)-5a,7a-dimethyl-3-oxo-N-phenyl-1,1a,
3,4,5,5a,5b,6,7,7a,8,9,10,10a,10b,10c-hexadecahydro-cyclopenta[a]cyclopro-
pa[1]phenanthrene-8-carboxamide
MS (M.sup.++H) 472.2423.
EXAMPLE 28
Oral Composition
As a specific embodiment of an oral composition of a compound of
this invention, 50 mg of a compound of the present invention is
formatted with sufficient finely divided lactose to provide a total
amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
EXAMPLE 29
Transdermal Patch Formulation
TABLE-US-00002 Ingredient Amount Compound of formula I 40 g
Silicone fluid 45 g Colloidal silicone dioxide 2.5 g
The silicone fluid and compound of structural formula I are mixed
together and the colloidal silicone dioxide is added to increase
viscosity. The material is then dosed into a subsequently heat
sealed polymeric laminate comprised of the following: polyester
release liner, skin contact adhesive composed of silicone or
acrylic polymers, a control membrane which is a polyolefin (e.g.
polyethylene, polyvinyl acetate or polyurethane), and an
impermeable backing membrane made of a polyester multilaminate. The
resulting laminated sheet is then cut into 10 cm.sup.2 patches. For
100 Patches.
EXAMPLE 30
Suppository
TABLE-US-00003 Ingredient Amount Compound of structural formula I
25 g Polyethylene glycol 1000 1481 g Polyethylene glycol 4000 494
g
The polyethylene glycol 1000 and polyethylene glycol 4000 are mixed
and melted. The compound of structural formula I is mixed into the
molten mixture, poured into molds and allowed to cool. For 1000
suppositories.
EXAMPLE 31
Injectable Solution
TABLE-US-00004 Ingredient Amount Compound of structural formula I 5
g Buffering agents q.s. Propylene glycol 400 mg Water for injection
600 mL
The compound of structural formula I and buffering agents are
dissolved in the propylene glycol at about 50.degree. C. The water
for injection is then added with stirring and the resulting
solution is filtered, filled into ampules, sealed and sterilized by
autoclaving. For 1000 Ampules.
EXAMPLE 32
Injectable Solution
TABLE-US-00005 Ingredient Amount Compound of structural formula I 5
g Buffering agents q.s. Magnesium sulfate heptahydrate 100 mg Water
for injection 880 mL
The compound of structural formula I, magnesium sulfate
heptahydrate and buffering agents are dissolved in the water for
injection with stirring, and the resulting solution is filtered,
filled into ampoules, sealed and sterilized by autoclaving. For
1000 Ampoules.
The following assays were used to characterize the activity of the
tissue selective androgen receptor modulators of the present
invention.
In vitro and in vivo Assays for Identification of Compounds with
Sarm Activity
1. Hydroxylapatite-based Radioligand Displacement Assay of Compound
Affinity for Endogenously Expressed AR
Materials:
Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM
beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2) 50% HAP
Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM Tris, pH
8.0 and 1 mM EDTA. Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM
EDTA and 1 mM EGTA. 95% EtOH Methyltrienolone,
[17.alpha.-methyl-.sup.3H], (R1881*); NEN NET590 Methyltrienolone
(R1881), NEN NLP005 (dissolve in 95% EtOH) Dihydrotestosterone
(DHT) [1,2,4,5,6,7-.sup.3H(N)] NEN NET453 Hydroxylapatite Fast
Flow; Calbiochem Cat#391947 Molybdate=Molybdic Acid (Sigma, M1651)
MDA-MB-453 Cell Culture Media:
TABLE-US-00006 RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO.sub.3, 2
mM L-glutamine In 500 mL of complete media Final conc. 10 mL (1 M
Hepes) 20 mM 5 mL (200 mM L-glu) 4 mM 0.5 mL (10 mg/mL human
insulin) 10 .mu.g/mL in 0.01 N HCl Calbiochem#407694-S) 50 mL FBS
(Sigma F2442) 10% 1 mL (10 mg/mL Gentamicin 20 .mu.g/mL
Gibco#15710-072)
Cell Passaging:
Cells (Hall R. E., et al., European Journal of Cancer, 30A: 484-490
(1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA is
diluted in the same PBS 1:10. The cell layers are rinsed with
1.times. Trypsin, extra Trypsin is poured out, and the cell layers
are incubated at 37.degree. C. for .about.2 min. The flask is
tapped and checked for signs of cell detachment. Once the cells
begin to slide off the flask, the complete media is added to kill
the trypsin. The cells are counted at this point, then diluted to
the appropriate concentration and split into flasks or dishes for
further culturing (Usually 1:3 to 1:6 dilution).
Preparation of MDA-MB-453 Cell Lysate
When the MDA cells are 70 to 85% confluent, they are detached as
described above, and collected by centrifuging at 1000 g for 10 min
at 4.degree. C. The cell pellet is washed twice with TEGM (10 mM
Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM
Sodium Molybdate, pH 7.2). After the final wash, the cells are
resuspended in TEGM at a concentration of 10.sup.7 cells/mL. The
cell suspension is snap frozen in liquid nitrogen or ethanol/dry
ice bath and transferred to -80.degree. C. freezer on dry ice.
Before setting up the binding assay, the frozen samples are left on
ice-water to just thaw (.about.1 hr). Then the samples are
centrifuged at 12,500 g to 20,000 g for 30 min at 4.degree. C. The
supernatant is used to set-up assay right away. If using 50 .mu.L
of supernatant, the test compound can be prepared in 50 .mu.L of
the TEGM buffer.
Procedure for Multiple Compound Screening:
1.times. TEGM buffer is prepared, and the isotope-containing assay
mixture is prepared in the following order: EtOH (2% final
concentration in reaction), .sup.3H-R1881 or .sup.3H-DHT (0.5 nM
final Conc. in reaction) and 1.times. TEGM. [eg. For 100 samples,
200 .mu.L (100.times.2) of EtOH+4.25 .mu.L of 1:10 .sup.3H-R1881
stock+2300 .mu.L (100.times.23) 1.times. TEGM]. The compound is
serially diluted, e.g., if starting final conc. is 1 .mu.M, and the
compound is in 25 .mu.L of solution, for duplicate samples, 75
.mu.L of 4.times.1 .mu.M solution is made and 3 .mu.L of 100 .mu.M
is added to 72 .mu.L of buffer, and 1:5 serial dilution.
25 .mu.L of .sup.3H-R1881 trace and 25 .mu.L compound solution are
first mixed together, followed by addition of 50 .mu.L receptor
solution. The reaction is gently mixed, spun briefly at about 200
rpm and incubated at 4.degree. C. overnight. 100 .mu.L of 50% HAP
slurry is prepared and added to the incubated reaction which is
then vortexed and incubated on ice for 5 to 10 minutes. The
reaction mixture is vortexed twice more to resuspend HAP while
incubating reaction. The samples in 96-well format are then washed
in wash buffer using The FilterMate.TM. Universal Harvester plate
washer (Packard). The washing process transfers HAP pellet
containing ligand-bound expressed receptor to Unifilter-96 GF/B
filter plate (Packard). The HAP pellet on the filter plate is
incubated with 50 .mu.L of MICROSCINT (Packard) scintillint for 30
minutes before being counted on the TopCount microscintillation
counter (Packard). IC.sub.50s are calculated using R1881 as a
reference. Tissue selective androgen receptor modulators of the
present invention displayed IC.sub.50 values of 1 micromolar or
less.
2. MMP1 Promoter Suppression, Transient Transfection Assay
(TRAMPS)
HepG2 cells are cultured in phenol red free MEM containing 10%
charcoal-treated FCS at 37 C with 5% CO.sub.2. For transfection,
cells are plated at 10,000 cells/well in 96 well white, clear
bottom plates. Twenty four hours later, cells are co-transfected
with a MMP1 promoter-luciferase reporter construct and a rhesus
monkey expression construct (50:1 ratio) using FuGENE6 transfection
reagent, following the protocol recommended by manufacturer. The
MMP1 promoter-luciferase reporter construct is generated by
insertion of a human MMP1 promoter fragment (-179/+63) into pGL2
luciferase reporter construct (Promega) and a rhesus monkey AR
expression construct is generated in a CMV-Tag2B expression vector
(Stratagene). Cells are further cultured for 24 hours and then
treated with test compounds in the presence of 100 nM
phorbol-12-myristate-13-acetate (PMA), used to increase the basal
activity of MMP1 promoter. The compounds are added at this point,
at a range of 1000 nM to 0.03 nM, 10 dilutions, at a concentration
on 10.times., 1/10th volume (example: 10 microliters of ligand at
10.times. added to 100 microliters of media already in the well).
Cells are further cultured for an additional 48 hours. Cells are
then washed twice with PBS and lysed by adding 70 .mu.L of Lysis
Buffer (1.times., Promega) to the wells. The luciferase activity is
measured in a 96-well format using a 1450 Microbeta Jet (Perkin
Elmer) luminometer. Activity of test compounds is presented as
suppression of luciferase signal from the PMA-stimulated control
levels. EC.sub.50 and Emax values are reported. Tissue selective
androgen receptor modulators of the present invention activate
repression typically with submicromolar EC.sub.50 values and Emax
values greater than about 50%.
References:
a. Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A,
"Fibroblast growth factor receptor signaling activates the human
interstitial collagenase promoter via the bipartite Ets-AP1
element," Mol. Endocrinol. 11: 1129-44 (1997). b. Schneikert J,
Peterziel H, Defossez P A, Klocker H, Launoit Y, Cato A C,
"Androgen receptor-Ets protein interaction is a novel mechanism for
steroid hormone-mediated down-modulation of matrix
metalloproteinase expression," J. Biol. Chem. 271: 23907-23913
(1996). 3. A Mammalian Two-Hybrid Assay for the Ligand-induced
Interaction of N-Terminus and C-Terminus Domains of the Androgen
Receptor (Agonist Mode)
This assay assesses the ability of AR agonists to induce the
interaction between the N-terminal domain (NTD) and C-terminal
domain (CTD) of rhAR that reflects the in vivo virilizing potential
mediated by activated androgen receptors. The interaction of NTD
and CTD of rhAR is quantified as ligand induced association between
a Gal4DBD-rhARCTD fusion protein and a VP16-rhARNTD fusion protein
as a mammalian two-hybrid assay in CV-1 monkey kidney cells.
The day before transfection, CV-1 cells are trypsinized and
counted, and then plated at 20,000 cells/well in 96-well plates or
larger plates (scaled up accordingly) in DMEM+10% FCS. The next
morning, CV-1 cells are cotransfected with pCBB1 (Gal4DBD-rhARLBD
fusion construct expressed under the SV40 early promoter), pCBB2
(VP16-rhAR NTD fusion construct expressed under the SV40 early
promoter) and pFR (Gal4 responsive luciferase reporter, Promega)
using LIPOFECTAMINE PLUS reagent (GIBCO-BRL) following the
procedure recommended by the vendor. Briefly, DNA admixture of 0.05
.mu.g pCBB1, 0.05 .mu.g pCBB2 and 0.1 .mu.g of pFR is mixed in 3.4
.mu.L OPTI-MEM (GIBCO-BRL) mixed with "PLUS Reagent" (1.6 .mu.L,
GIBCO-BRL) and incubated at room temperature (RT) for 15 min to
form the pre-complexed DNA.
For each well, 0.4 .mu.L LIPOFECTAMINE Reagent (GBCO-BRL) is
diluted into 4.6 .mu.L OPTI-MEM in a second tube and mixed to form
the diluted LIPOFECTAMINE Reagent. The pre-complexed DNA (above)
and the diluted LIPOFECTAMINE Reagent (above) are combined, mixed
and incubated for 15 min at RT. The medium on the cells is replaced
with 40 .mu.L /well OPTI-MEM, and 10 .mu.L DNA-lipid complexes are
added to each well. The complexes are mixed into the medium gently
and incubated at 37.degree. C. at 5% CO.sub.2 for 5 h. Following
incubation, 200 .mu.L /well D-MEM and 13% charcoal-stripped FCS are
added, followed by incubation at 37.degree. C. at 5% CO.sub.2.
After 24 hours, the test compounds are added at the desired
concentration(s) (1 nM-10 .mu.M). Forty eight hours later,
luciferase activity is measured using LUC-Screen system (TROPIX)
following the manufacturer's protocol. The assay is conducted
directly in the wells by sequential addition of 50 .mu.L each of
assay solution 1 followed by assay solution 2. After incubation for
40 minutes at room temperature, luminescence is directly measured
with 2-5 second integration.
Activity of test compounds is calculated as the E.sub.max relative
to the activity obtained with 3 nM R1881. Typical tissue-selective
androgen receptor modulators of the present invention display weak
or no agonist activity in this assay with less than 50% agonist
activity at 10 micromolar.
Reference:
He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M,
"Activation function in the human androgen receptor ligand binding
domain mediates inter-domain communication with the NH(2)-terminal
domain," J. Biol. Chem. 274: 37219-37225 (1999). 4. A Mammalian
Two-Hybrid Assay for Inhibition of Interaction between N-Terminus
and C-Terminus Domains of Androgen Receptor (Antagonist Mode)
This assay assesses the ability of test compounds to antagonize the
stimulatory effects of R1881 on the interaction between NTD and CTD
of rhAR in a mammalian two-hybrid assay in CV-1 cells as described
above.
Forty eight hours after transfection, CV-1 cells are treated with
test compounds, typically at 10 .mu.M, 3.3 .mu.M, 1 .mu.M, 0.33
.mu.M, 100 nM, 33 nM, 10 nM, 3.3 nM and 1 nM final concentrations.
After incubation at 37.degree. C. at 5% CO.sub.2 for 10 -30
minutes, an AR agonist methyltrienolone (R1881) is added to a final
concentration of 0.3 nM and incubated at 37.degree. C. Forty-eight
hours later, luciferase activity is measured using LUC-Screen
system (TROPIX) following the protocol recommended by the
manufacturer. The ability of test compounds to antagonize the
action of R1881 is calculated as the relative luminescence compared
to the value with 0.3 nM R1881 alone.
SARM compounds of the present invention typically displayed
antagonist activity in the present assay with IC.sub.50 values less
than 1 micromolar.
5. Trans-Activation Modulation of Androgen Receptor (TAMAR)
This assay assesses the ability of test compounds to control
transcription from the MMTV-LUC reporter gene in MDA-MB-453 cells,
a human breast cancer cell line that naturally expresses the human
AR. The assay measures induction of a modified MMTV LTR/promoter
linked to the LUC reporter gene.
20,000 to 30,000 cells/well are plated in a white, clear-bottom
96-well plate in "Exponential Growth Medium" which consists of
phenol red-free RPMI 1640 containing 10% FBS, 4 mM L-glutamine, 20
mM HEPES, 10 ug/mL human insulin, and 20 ug/mL gentamicin.
Incubator conditions are 37.degree. C. and 5% CO.sub.2. The
transfection is done in batch mode. The cells are trypsinized and
counted to the right cell number in the proper amount of fresh
media, and then gently mixed with the Fugene/DNA cocktail mix and
plated onto the 96-well plate. All the wells receive 200 .mu.l of
medium+lipid/DNA complex and are then incubated at 37.degree. C.
overnight. The transfection cocktail consists of serum-free
Optimem, Fugene6 reagent and DNA. The manufacturer's (Roche
Biochemical) protocol for cocktail setup is followed. The lipid
(.mu.l) to DNA (.mu.g) ratio is approximately 3:2 and the
incubation time is 20 min at room temperature. Sixteen to 24 hrs
after transfection, the cells are treated with test compounds such
that the final DMSO (vehicle) concentration is <3%. The cells
are exposed to the test compounds for 48 hrs. After 48 hrs, the
cells are lysed by a Promega cell culture lysis buffer for 30-60
min and then the luciferase activity in the extracts is assayed in
the 96-well format luminometer.
Activity of test compounds is calculated as the E.sub.max relative
to the activity obtained with 100 nM R1881.
References:
a. R. E. Hall, et al., "MDA-MB-453, an androgen-responsive human
breast carcinoma cell line with high androgen receptor expression,"
Eur. J. Cancer, 30A: 484-490 (1994). b. R. E. Hall, et al.,
"Regulation of androgen receptor gene expression by steroids and
retinoic acid in human breast-cancer cells," Int. J. Cancer., 52:
778-784 (1992). 6. In Vivo Prostate Assay
Male Sprague-Dawley rats aged 9-10 weeks, the earliest age of
sexual maturity, are used in prevention mode. The goal is to
measure the degree to which androgen-like compounds delay the rapid
deterioration (.about.-85%) of the ventral prostate gland and
seminal vesicles that occurs during a seven day period after
removal of the testes (orchiectomy [ORX]).
Rats are orchiectomized (ORX). Each rat is weighed, then
anesthetized by isoflurane gas that is maintained to effect. A 1.5
cm anteroposterior incision is made in the scrotum. The right
testicle is exteriorized. The spermatic artery and vas deferens are
ligated with 4.0 silk 0.5 cm proximal to the testicle. The testicle
is freed by one cut of a small surgical scissors distal to the
ligation site. The tissue stump is returned to the scrotum. The
same is repeated for the left testicle. When both stumps are
returned to the scrotum, the scrotum and overlying skin are sutured
closed with 4.0 silk. For Sham-ORX, all procedures excepting
ligation and scissors cutting are completed. The rats fully recover
consciousness and full mobility within 10-15 minutes.
A dose of test compound is administered subcutaneously or orally to
the rat immediately after the surgical incision is sutured.
Treatment continues for an additional six consecutive days.
Necropsy and Endpoints:
The rat is first weighed, then anesthetized in a CO.sub.2 chamber
until near death. Approximately 5 ml whole blood is obtained by
cardiac puncture. The rat is then examined for certain signs of
death and completeness of ORX. Next, the ventral portion of the
prostate gland is located and blunt dissected free in a highly
stylized fashion. The ventral prostate is blotted dry for 3-5
seconds and then weighed (VPW). Finally, the seminal vesicle is
located and dissected free. The ventral seminal vesicle is blotted
dry for 3-5 seconds and then weighed (SVWT).
Primary data for this assay are the weights of the ventral prostate
and seminal vesicle. Secondary data include serum LH (luteinizing
hormone) and FSH (follicle stimulating hormone), and possible serum
markers of bone formation and virilization. Data are analyzed by
ANOVA plus Fisher PLSD post-hoc test to identify intergroup
differences. The extent to which test compounds inhibit ORX-induced
loss of VPW and SVWT is assessed.
7. In Vivo Bone Formation Assay:
Female Sprague-Dawley rats aged 7-10 months are used in treatment
mode to simulate adult human females. The rats have been
ovariectomized (OVX) 75-180 days previously, to cause bone loss and
simulate estrogen deficient, osteopenic adult human females.
Pre-treatment with a low dose of a powerful anti-resorptive,
alendronate (0.0028 mpk SC, 2.times./wk) is begun on Day 0. On Day
15, treatment with test compound is started. Test compound
treatment occurs on Days 15-31 with necropsy on Day 32. The goal is
to measure the extent to which androgen-ike compounds increase the
amount of bone formation, shown by increased fluorochrome labeling,
at the periosteal surface.
In a typical assay, nine groups of seven rats each are studied.
On Days 19 and 29 (fifth and fifteenth days of treatment), a single
subcutaneous injection of calcein (8 mg/kg) is given to each
rat.
Necropsy and Endpoints:
The rat is first weighed, then anesthetized in a CO.sub.2 chamber
until near death. Approximately 5 mL whole blood is obtained by
cardiac puncture. The rat is then examined for certain signs of
death and completeness of OVX. First, the uterus is located, blunt
dissected free in a highly stylized fashion, blotted dry for 3-5
seconds and then weighed (UW). The uterus is placed in 10%
neutral-buffered formalin. Next, the right leg is disarticulated at
the hip. The femur and tibia are separated at the knee,
substantially defleshed, and then placed in 70% ethanol.
A 1-cm segment of the central right femur, with the femoral
proximal-distal midpoint ats center, is placed in a scintillation
vial and dehydrated and defatted in graded alcohols and acetone,
then introduced to solutions with increasing concentrations of
methyl methacrylate. It is embedded in a mixture of 90% methyl
methacrylate:10% dibutyl phthalate, that is allowed to polymerize
over a 48-72 hr period. The bottle is cracked and the plastic block
is trimmed into a shape that conveniently fits the vice-like
specimen holder of a Leica 1600 Saw Microtome, with the long axis
of the bone prepared for cross-sectioning. Three cross-sections of
85 .mu.m thickness are prepared and mounted on glass slides. One
section from each rat that approximates the midpoint of the bone is
selected and blind-coded. The periosteal surface of each section is
assessed for total periosteal surface, single fluorochrome label,
double fluorochrome label, and interlabel distance.
Primary data for this assay are the percentage of periosteal
surface bearing double label and the mineral apposition rate
(interlabel distance(.mu.m)/10 d), semi-independent markers of bone
formation. Secondary data include uterus weight and histologic
features. Tertiary endpoints may include serum markers of bone
formation and virilization. Data are analyzed by ANOVA plus Fisher
PLSD post-hoc test to identify intergroup differences. The extent
to which test compounds increase bone formation endpoint are
assessed.
While the foregoing specification teaches the principles of the
present invention, with examples provided for the purpose of
illustration, it is understood that the practice of the invention
encompasses all of the usual variations, adoptions, or
modifications, as being within the scope of the following claims
and their equivalents.
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